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Watanabe Y, Someya T, Nawa H. Cytokine hypothesis of schizophrenia pathogenesis: evidence from human studies and animal models. Psychiatry Clin Neurosci 64: 217-230
Abstract
The pathogenesis of schizophrenia has yet to be fully characterized. Gene-environment interactions have been found to play a crucial role in the vulnerability to this disease. Among various environmental factors, inflammatory immune processes have been most clearly implicated in the etiology and pathology of schizophrenia. Cytokines, regulators of immune/inflammatory reactions and brain development, emerge as part of a common pathway of genetic and environmental components of schizophrenia. Maternal infection, obstetric complications, neonatal hypoxia and brain injury all recruit cytokines to mediate inflammatory processes. Abnormal expression levels of specific cytokines such as epidermal growth factor, interleukins (IL) and neuregulin-1 are found both in the brain and peripheral blood of patients with schizophrenia. Accordingly, cytokines have been proposed to transmit peripheral immune/inflammatory signals to immature brain tissue through the developing blood-brain barrier, perturbing structural and phenotypic development of the brain. This cytokine hypothesis of schizophrenia is also supported by modeling experiments in animals. Animals treated with specific cytokines of epidermal growth factor, IL-1, IL-6, and neuregulin-1 as embryos or neonates exhibit schizophrenia-like behavioral abnormalities after puberty, some of which are ameliorated by treatment with antipsychotics. In this review, we discuss the neurobiological mechanisms underlying schizophrenia and novel antipsychotic candidates based on the cytokine hypothesis.
... These tight interactions and pathological connections between EGF signaling and the TLR system play a crucial role in current respiratory syncytial (RS)-virus-induced and COVID-19-induced cytokine storm and pneumonia [27,28]. Given the interactions between these systems, the EGF family and its signaling are augmented in the immuneinflammatory hypothesis of schizophrenia [29][30][31][32][33], potentially suggesting a substantial impact on the later risk of schizophrenia or other psychiatric diseases following the COVID-19 pandemic [34][35][36]. At present, there is no clear boundary between growth factors and inflammatory cytokines. ...
... immune-inflammatory hypothesis of schizophrenia [29][30][31][32][33], potentially suggesting a substantial impact on the later risk of schizophrenia or other psychiatric diseases following the COVID-19 pandemic [34][35][36]. At present, there is no clear boundary between growth factors and inflammatory cytokines. ...
... In addition to the genetic hypothesis for schizophrenia, many epidemiological studies have raised various types of environmental hypotheses for schizophrenia, such as the immune-inflammatory hypothesis [31,[66][67][68]. Among these, we tested the immuneinflammatory hypothesis to produce animal models for schizophrenia; prenatal or perinatal inflammatory cytokines perturb normal brain development and/or circuit organization, leading to abnormal neurocognition and emotions in schizophrenia [29][30][31]69,70]. Accordingly, we tested this hypothesis at the molecular level, challenging pregnant mice and neonatal rats with various inflammatory cytokines [71]. ...
Epidermal growth factor (EGF) and its homologs, such as neuregulins, bind to ErbB (Her) receptor kinases and regulate glial differentiation and dopaminergic/GABAergic maturation in the brain and are therefore implicated in schizophrenia neuropathology involving these cell abnormalities. In this review, we summarize the biological activities of the EGF family and its neuropathologic association with schizophrenia, mainly overviewing our previous model studies and the related articles. Transgenic mice as well as the rat/monkey models established by perinatal challenges of EGF or its homologs consistently exhibit various behavioral endophenotypes relevant to schizophrenia. In particular, post-pubertal elevation in baseline dopaminergic activity may illustrate the abnormal behaviors relevant to positive and negative symptoms as well as to the timing of this behavioral onset. With the given molecular interaction and transactivation of ErbB receptor kinases with Toll-like receptors (TLRs), EGF/ErbB signals are recruited by viral infection and inflammatory diseases such as COVID-19-mediated pneumonia and poxvirus-mediated fibroma and implicated in the immune–inflammatory hypothesis of schizophrenia. Finally, we also discuss the interaction of clozapine with ErbB receptor kinases as well as new antipsychotic development targeting these receptors.
... po ich noworodkowym okresie rozwoju (14-22 dni po urodzeniu), stwierdzono istotnie ograniczone przenikanie cytokin przez BBB względem okresu noworodkowego. W przypadku tych samych młodych osobników po okresie ich pokwitania nie zaobserwowano zmian zachowania mogących odpowiadać schizofrenii [15,16]. Wydaje się więc, że aby zaburzenia behawioralne przypominające schizofrenię mogły się ujawnić po okresie dojrzewania, cytokiny podawane obwodowo w modelach zwierzęcych muszą przenikać przez BBB w okresie noworodkowym. ...
... Wydaje się więc, że aby zaburzenia behawioralne przypominające schizofrenię mogły się ujawnić po okresie dojrzewania, cytokiny podawane obwodowo w modelach zwierzęcych muszą przenikać przez BBB w okresie noworodkowym. Taka koncepcja wspiera neurorozwojową teorię tłumaczącą etiologię schizofrenii [16]. Na podstawie ostatnio przeprowadzonych badań genetycznych zakłada się, że geny mające związek z mechanizmami odpowiedzi zapalnej stanowią czynnik predysponujący do rozwoju schizofrenii [16,17]. ...
... Taka koncepcja wspiera neurorozwojową teorię tłumaczącą etiologię schizofrenii [16]. Na podstawie ostatnio przeprowadzonych badań genetycznych zakłada się, że geny mające związek z mechanizmami odpowiedzi zapalnej stanowią czynnik predysponujący do rozwoju schizofrenii [16,17]. W badaniach neuroobrazowych oraz neuropatologicznych nie zaobserwowano obecności istotnych zmian zapalnych CUN w przebiegu już zdiagnozowanej schizofrenii [18]. ...
Schizofrenia jest zaburzeniem psychicznym o złożonej etiopatogenezie, tłumaczonej przez kilka wciąż rozwijanych teorii. Ich znajomość może mieć znaczenie przy wyborze odpowiedniego leczenia, co przekłada się na sukces terapeutyczny. Obecnie opracowywane są różne strategie, dzięki którym można w pewnym zakresie dostosowywać terapię do indywidualnych potrzeb chorych, wpływając przez to na zoptymalizowanie efektu leczniczego i zminimalizowanie działań niepożądanych. Kwestia personalizacji terapii przekłada się na lepszą współpracę pomiędzy lekarzem i chorym. Zaangażowanie obydwu stron w proces leczenia, podobnie jak w terapii innych zaburzeń psychicznych ma kluczowe znaczenie dla jego skuteczności. Dostępne metody terapeutyczne w dalszym ciągu nie przynoszą zadowalających rezultatów w redukcji objawów negatywnych czy zaburzeń poznawczych, występujących w przebiegu schizofrenii. Aktualnie do osiągnięcia satysfakcjonujących wyników badań może przyczynić się nie tylko rozwój psychiatrii, ale i gałęzi pokrewnych medycynie, takich jak farmakogenetyka czy biologia molekularna. Zasadne wydaje się więc dążenie do opracowania nowych strategii leczenia. Krótkie przedstawienie najbardziej obiecujących terapii jest celem niniejszego przeglądu literatury. Omówiono w nim leczenie farmakologiczne (karyprazyna, paliperydon, lurazydon, brekspiprazol, lumateperon), magnetyczną stymulację przezczaszkową, psychoterapię oraz terapie poprawiające funkcje poznawcze. Poruszono także kwestię farmakogenetyki schizofrenii.
... Targeted antibody therapies designed to reduce specific cytokines, such as EGF, IL-1, or IL-6, have been employed to manage severe cases and reduce mortality [19,30,31]. It is noteworthy that these cytokines have also been implicated in the pathogenesis of schizophrenia [32]. ...
... Building on these clinical insights as well as on the cytokine hypothesis for schizophrenia [21,32], animal models for schizophrenia have been established in rodents and cynomolgus monkeys using various administration protocols as well as with other EGFR ligands [143][144][145]. EGF administration to the periphery of neonatal animals, but not to that of pregnant dams or adult animals, results in the postpubertal alterations in animal behaviors of their offspring such as prepulse inhibition, social interaction, latent inhibition of fear learning and working memory [132] (Figure 4). ...
COVID‐19 exhibits not only respiratory symptoms but also neurological/psychiatric symptoms rarely including delirium/psychosis. Pathological studies on COVID‐19 provide evidence that the cytokine storm, in particular (epidermal growth factor) EGF receptor (EGFR, ErbB1, Her1) activation, plays a central role in the progression of viral replication and lung fibrosis. Of note, SARS‐CoV‐2 virus (specifically, S1 spike domain) mimics EGF and directly transactivates EGFR, preceding the inflammatory process. In agreement, the anticancer drugs targeting EGFR such as Nimotuzumab and tyrosine kinase inhibitors are markedly effective on COVID‐19. However, these data might raise a provisional caution regarding implication of psychiatric disorder such as schizophrenia. The author's group has been investigating the etiologic and neuropathologic associations of EGFR signaling with schizophrenia. There are significant molecular associations between schizophrenia and EGFR ligand levels in blood as well as in the brain. In addition, perinatal challenges of EGFR ligands and intraventricular administration of EGF to rodents and monkeys both resulted in severe behavioral and/or electroencephalographic endophenotypes relevant to this disorder. These animal models also display postpubertal abnormality in soliloquy‐like self‐vocalization as well as in intercortical functional connectivity. Here, we discuss neuropsychiatric implication of coronavirus infection and its interaction with the EGFR system, by searching related literatures in PubMed database as of the end of 2023.
... Although the pathological mechanisms of schizophrenia still need to be elucidated, several lines of evidence over the last decades have implicated the immune system and the inflammatory mediators in the etiopathogenesis of the disease [1][2][3][4]. Within this context, cytokine alterations have been extensively investigated [5][6][7][8][9][10][11][12]. It has been suggested that pro-inflammatory cytokines' augmentation in the central nervous system can lead to impaired brain function [13]. ...
... There is an emerging literature reporting an interaction between cytokine network and antipsychotic treatment for acute and chronic schizophrenia patients [4,[26][27][28][29][30][31][32][33]. ...
The interplay between the cytokine network and antipsychotic treatment in schizophrenia remains poorly understood. This study aimed to investigate the impact of psychotropic medications on serum levels of IFN-γ, IL-4, TGF-β1, IL-17, and BAFF, and to explore their relationship with psychopathological features. We recruited 63 patients diagnosed with schizophrenia in the acute phase, all of whom were either drug-naïve or had been drug-free for at least three months. Serum levels of IL-4, IFN-γ, TGF-β1, IL-17, and BAFF were measured at baseline and after six months of antipsychotic treatment. The severity of symptoms was assessed using the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Positive Symptoms (SAPS), and the Scale for the Assessment of Negative Symptoms (SANS). Fifty-two patients completed the six-month follow-up for immunoassay analysis. Antipsychotic treatment led to a significant decrease in serum levels of IFN-γ, TGF-β1, and IL-17, alongside a significant increase in BAFF levels. Changes in IFN-γ were positively correlated with SANS scores and negatively correlated with Global Assessment of Functioning (GAF) scores. Changes in TGF-β1 were negatively correlated with GAF scores. Changes in BAFF were negatively correlated with SAPS scores. Multivariable regression models were used to explore the association between cytokine level changes (IL-17, BAFF, IFN-γ, and TGF-β1) and independent variables, including demographic (gender, age), behavioral (tobacco use), clinical (schizophrenia type, disease course, date of onset, prior treatment), and biological (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)) factors, as well as standardized assessment scores. No significant associations were found, except for a significant negative correlation between TGF-β1 changes and GAF scores, as well as a positive correlation with age. Interestingly, advanced statistical analyses revealed that only changes in IL-17 and BAFF levels were significantly associated with antipsychotic treatment. Our findings suggest that antipsychotic drugs exert both pro- and anti-inflammatory effects on the cytokine network. The observed modulation of IL-17 and BAFF highlights their potential as future therapeutic targets in schizophrenia.
... Involvement of the complement system was demonstrated in various neurodegenerative disorders such as Alzheimer's disease (123,124), Huntington's disease (125), Parkinson's disease (126), Pick's disease (127) and amyotrophic lateral sclerosis (ALS) (128). Moreover, activation of the complement system has been demonstrated in schizophrenia (129)(130)(131)(132)(133) and autism (134)(135)(136), and it is believed that the complement system could contribute to symptomatology of those disorders. For instance, association of C1qB gene polymorphism with schizophrenia was demonstrated in an Armenian population and it was suggested that the"C1qB gene may be considered as a relevant candidate for susceptibility to schizophrenia." ...
... Few studies revealed that clozapine affects the increase of IL-6 in the plasma during the 2 weeks, but not the longer treatment (125)(126)(127)(128), while other, comprehensive studies showed that atypical antipsychotic risperidone or the typical antipsychotic haloperidol do not significantly affect serum levels of IL-6 in patients with schizophrenia (117,129). Further, decrease of IL-6 in the plasma of patients with exacerbation of schizophrenia was shown after discontinuation of the haloperidol therapy (130). The peripheral low-grade inflammation was observed in animal model after olanzapine treatment, correlated with upregulation of IL-6 in hypothalamus and adipose tissue (white and brown), and enhanced average size of adipocyte and macrophage infiltration level (131). ...
... It has been reported that cytokines and immune cells can in part cross the blood-brain barrier and bind to the receptor in the brain. Then, they disrupt intracellular signal transduction, affecting the formation of neural circuitry and maturation of synapses, and further contributing to impaired brain function 21 . Compromised integrity of the blood-brain barrier (BBB) has been reported, and immune cell infiltration has been found in SZ 22,23 . ...
Patients with schizophrenia with early onset age have been shown to exhibit more severe negative symptoms. Genetic, biomarker, postmortem brain, and imaging studies indicate the involvement of immune abnormalities in the pathophysiology of schizophrenia. In this study, we examined the moderating role of early onset on the associations between clinical symptoms and neutrophil-to-lymphocyte ratio (NLR) in medication-naïve first-episode schizophrenia (MNFES). A total of 97 MNFES patients were recruited. Neutrophil (NEU), LYM, and NLR values were compared between early-onset (EO) and non-early-onset (non-EO) patients with schizophrenia to explore the potential influence of EO on the correlations between NLR and symptoms. The results showed no differences in NEU and NLR values between the EO and non-EO groups. In the EO group, NEU and NLR values significantly correlated with general psychopathology and total score (all p < 0.05), whereas lymphocyte counts were not correlated with symptoms of schizophrenia. NEU and NLR were not associated with symptoms in the non-EO group. Linear regression analysis in the EO group revealed that NEU or NLR values were a predictive biomarker for the clinical symptoms. Our study indicates that EO patients had greater severe negative symptoms compared with non-EO patients. In addition, onset age mediates the relationships of NEU and NLR values with clinical symptoms, suggesting that an immune disturbance, particularly increased innate immune response in EO patients, may be involved in the psychophysiology of schizophrenia.
... It disrupts normal brain functions and is diagnosed based on a spectrum of symptoms, including delusions, hallucinations, social withdrawal, and cognitive deficits [18]. Despite various proposed hypotheses about its onset and progression, the incidence and cure rates for schizophrenia have seen little improvement [19][20][21]. In recent studies, mitochondria, the cellular powerhouses, have come under scrutiny, especially concerning their dynamics in schizophrenia [22]. ...
Background
Increasingly studies highlight the crucial role of the ancestral retrovirus envelope protein ERVWE1 in the pathogenic mechanisms of schizophrenia, a severe psychiatric disorder affecting approximately 1% of the global population. Recent studies also underscore the significance of circular RNAs (circRNAs), crucial for neurogenesis and synaptogenesis, in maintaining neuronal functions. However, the precise relationship between ERVWE1 and circRNAs in the etiology of schizophrenia remains elusive.
Results
This study observed elevated levels of hsa_circ_0001810 (circ_0001810) in the blood samples of schizophrenia patients, displaying a significant positive correlation with ERVWE1 expression. Interestingly, in vivo studies demonstrated that ERVWE1 upregulated circ_0001810 in neuronal cells. Circ_0001810, acting as a competing endogenous RNA (ceRNA), bound to miR-1197 and facilitated the release of adenylate kinase 2 (AK2). The bioinformatics analysis of the schizophrenia datasets revealed increased levels of AK2 and enrichment of mitochondrial dynamics. Notably, miR-1197 was reduced in schizophrenia patients, while AK2 levels were increased. Additionally, AK2 showed positive correlations with ERVWE1 and circ_0001810. Further studies demonstrated that AK2 led to mitochondrial dysfunction, characterized by loss of intracellular ATP, mitochondrial depolarization, and disruption of mitochondrial dynamics. Our comprehensive investigation suggested that ERVWE1 influenced ATP levels, promoted mitochondrial depolarization, and disrupted mitochondrial dynamics through the circ_0001810/AK2 pathway.
Conclusions
Circ_0001810 and AK2 were increased in schizophrenia and positively correlated with ERVWE1. Importantly, ERVWE1 triggered mitochondrial dysfunction through circ_0001810/miR-1197/AK2 pathway. Recent focus on the impact of mitochondrial dynamics on schizophrenia development had led to our discovery of a novel mechanism by which ERVWE1 contributed to the etiology of schizophrenia, particularly through mitochondrial dynamics. Moreover, these findings collectively proposed that circ_0001810 might serve as a potential blood-based biomarker for schizophrenia. Consistent with our previous theories, ERVWE1 is increasingly recognized as a promising therapeutic target for schizophrenia.
... Previous findings report that both SZ and BD patients are associated with the deregulation of the systemic cytokine's concentration. The main hypothesis is that the inflammatory condition may interfere specially in the blood and brain barrier permeability [48,49]. It is supposed that in both BD and SZ, a pro-inflammatory profile is present and, chronically, could promote pathological modification in the CNS way before the disease's onset. ...
Background
Bipolar disorder (BD) and schizophrenia (SZ) are the two main mental disorders with unknown etiology that significantly impact individuals’ quality of life. The potential pro-inflammatory role in their pathogenesis is postulated and Human Endogenous Retrovirus W (HERV-W) is an emerging candidate to modulate this pathogenic finding. HERVs, ancient retroviruses in the human genome, may play roles in inflammation and disease pathogenesis. Despite HERVs’ involvement in autoimmune diseases, their influence on mental disorders remains underexplored. Therefore, the aim of this study was to assess the level of HERV-W-env expression and the systemic inflammatory profile through the concentration of IL-2, IL-4, IL-6, IL-10, TNF-α and INF-γ cytokines in BD and SZ patients.
Results
All participants showed HERV-W-env expression, but its expression was higher in mental disorder patients ( p < 0.01) than in control. When separated, SZ individuals exhibited higher HERV-W expression than the control group ( p < 0.01). Higher serum levels of TNF-α and IL-10 were found in BD ( p = 0.0001 and p = 0.001, respectively) and SZ ( p = 0.01) and p = 0.01, respectively) than in the control group, while SZ showed decreased levels IFN-γ and IL-2 as compared to controls ( p = 0.05) and BD patients ( p = 0.05), respectively. Higher TNF-α/IL-4 and TNF-α/IL-10 ratios, and lower IFN-γ/IL-10 were observed in BD and SZ patients than controls. Significant negative correlation between HERV-W-env expression and IL-10 ( r =-0.47 p < 0.05), as well as positive correlations between HERV-W-env expression and TNF-α/IL-10 or IFN-γ/IL-10 ratios ( r = 0.48 p < 0.05 and r = 0.46 p < 0.05, respectively) were found in BD patients.
Conclusion
These findings suggest not only a potential link between HERV-W-env expression both in BD and SZ, but also a possible involvement of systemic inflammatory status in BD patients.
... Treatment with ceftriaxone displayed anxiety-like, depression-like, and aggressive behaviors in treated mice when compared with controls ones . The evidence indicates the contribution of the microbiota as a relevant factor in the pathogenesis and progression of these psychiatric disorders (Benros et al. 2014;Berk et al. 2011;Dash et al. 2022;Watanabe et al. 2010). ...
The gut-brain axis is an essential communication pathway between the central nervous system (CNS) and the gastrointestinal tract. The human microbiota is composed of a diverse and abundant microbial community that compasses more than 100 trillion microorganisms that participate in relevant physiological functions such as host nutrient metabolism, structural integrity, maintenance of the gut mucosal barrier, and immunomodulation. Recent evidence in animal models has been instrumental in demonstrating the possible role of the microbiota in neurodevelopment, neuroinflammation, and behavior. Furthermore, clinical studies suggested that adverse changes in the microbiota can be considered a susceptibility factor for neurological disorders (NDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). In this review, we will discuss evidence describing the role of gut microbes in health and disease as a relevant risk factor in the pathogenesis of neurodegenerative disorders, including AD, PD, HD, and ALS.
... Dysregulation of IL-6 signaling is associated with inflammatory disorders as well as SZ. A potential pathological link between hyper-IL-6 signaling and SZ has been identified in clinical studies and animal models of SZ (Watanabe et al., 2010). LncRNAs have been recently implicated in the regulation of IL-6-related signaling and function, closely related with the development of a range of IL-6 dysregulated diseases (Zhang and Chu, 2019). ...
Schizophrenia (SZ), a complex and debilitating spectrum of psychiatric disorders, is now mainly attributed to multifactorial etiology that includes genetic and environmental factors. Long non-coding RNAs (lncRNAs) are gaining popularity as a way to better understand the comprehensive mechanisms beneath the clinical manifestation of SZ. Only in recent years has it been elucidated that mammalian genomes encode thousands of lncRNAs. Strikingly, roughly 30-40% of these lncRNAs are extensively expressed in different regions across the brain, which may be closely associated with SZ. The therapeutic and adverse effects of atypical antipsychotic drugs (AAPDs) are partially reflected by their role in the regulation of lncRNAs. This begs the question directly, do any lncRNAs exist as biomarkers for AAPDs treatment? Furthermore, we comprehend a range of mechanistic investigations that have revealed the regulatory roles for lncRNAs both involved in the brain and the periphery of SZ. More crucially, we also combine insights from a variety of signaling pathways to argue that lncRNAs probably play critical roles in SZ via their interactive downstream factors. This review provides a thorough understanding regarding dysregulation of lncRNAs, corresponding genetic alternations, as well as their potential regulatory roles in the pathology of SZ, which might help reveal useful therapeutic targets in SZ.
... Furthermore, they are involved in the modulation of synaptic plasticity. Therefore, an imbalance in interleukin levels represents vulnerability to immune inflammatory process and subsequently can cause an impairment of brain functions [47]. The most common explanation studied is the microglial activation, which triggers interleukin productions. ...
Atypical antipsychotic drugs such risperidone are selected for the first-line treatment of individuals with schizophrenia. In this sense, it has been observed that when risperidone is used frequently, it can induce changes in metabolism, which could alter pro-inflammatory cytokine levels. The aim of this systematic review was to evaluate the role of risperidone in interleukin levels of individuals with schizophrenia. The systematic search was performed in PubMed, Scopus, and EBSCO databases up to March 2023. Interleukin levels were evaluated in individuals with schizophrenia before and after treatment with risperidone and also compared with control groups. The most common interleukins analyzed before and after treatment with risperidone were IL-6, IL-17A, IL-10, IL-4, IL-2, IL-1B, and IL-8. With regard to case-control studies, we observed that the main interleukins evaluated were IL-2, IL-6, IL-1B, IL-12, IL-10, IL-4, and IL-8. Evidence indicates that individuals with schizophrenia who undergo a regular treatment with risperidone could trigger the release and circulation of pro-inflammatory interleukins and therefore, their concentration in plasma or serum increases. More studies are needed to evaluate more variables.
... The etiology of SZ remains unclear (1)(2)(3)(4)(5). Brain structural changes, such as reduced cortical thickness, have been demonstrated (6) that resemble those seen in advanced aging (7,8). ...
Brain structural abnormalities have been demonstrated in schizophrenia (SZ); these resemble those seen in typical aging, but are seen at younger ages. Furthermore, SZ is associated with accelerated global brain aging, as measured by brain structure-based brain predicted age difference (Brain-PAD). High heterogeneity exists in the degree of brain abnormalities in SZ, and individual differences may be related to levels of peripheral inflammation and may relate to cognitive deficits and negative symptoms. The goal of our study was to investigate the relationship between brain aging, peripheral inflammation, and symptoms of SZ. We hypothesized older brain-PAD in SZ vs. healthy comparison (HC) participants, as well as positive relationships of brain-PAD with peripheral inflammation markers and symptoms in SZ. We analyzed data from two cross-sectional studies in SZ (n = 26; M/F: 21/5) and HC (n = 28; 20/8) (22–64 years). Brain-PAD was calculated using a previously validated Gaussian process regression model applied to raw T1-weighted MRI data. Plasma levels of inflammatory biomarkers (CRP, Eotaxin, Fractalkine, IP10, IL6, IL10, ICAM1, IFNγ, MCP1, MIP1β, SAA, TNFα, VEGF, VCAM1) and cognitive and negative symptoms were assessed. We observed a higher brain-PAD in SZ vs. HC, and advanced brain age relative to chronological age was related to higher peripheral levels of TNFα in the overall group and in the SZ group; other inflammatory markers were not related to brain-PAD. Within the SZ group, we observed no association between cognitive or negative symptoms and brain-PAD. These results support our hypothesis of advanced brain aging in SZ. Furthermore, our findings on the relationship of the pro-inflammatory cytokine TNFα with higher brain-PAD of SZ are relevant to explain heterogeneity of brain ages in SZ, but we did not find strong evidence for cognitive or negative symptom relationships with brain-PAD.
... Based on the immune inflammatory hypothesis of schizophrenia [14][15][16] , we investigated animal models established by perinatal exposure to the cytokines epidermal growth factor (EGF) and neuregulin 1, which are implicated in obstetric complication or neonatal hypoxia [17][18][19] . Neonatal rats or mice that are challenged with EGF or neuregulin 1, which bind to ErbB receptors in the brain, later develop a variety of behavioral deficits relevant to schizophrenia [17][18][19][20][21] . ...
Rats elicit two types of ultrasonic vocalizations (USVs), positive (30–80 kHz; high pitch) and negative (10–30 kHz; low pitch) voices. As patients with schizophrenia often exhibit soliloquy-like symptoms, we explored whether an animal model for schizophrenia is similarly characterized by such self-triggered vocalizations. We prepared the animal model by administering an inflammatory cytokine, epidermal growth factor (EGF), to rat neonates, which later develop behavioral and electroencephalographic deficits relevant to schizophrenia. EGF model rats and controls at young (8–10 weeks old) and mature (12–14 weeks old) adult stages were subjected to acclimation, female pairing, and vocalization sessions. In acclimation sessions, low pitch USVs at the mature adult stage were more frequent in EGF model rats than in controls. In the vocalization session, the occurrences of low pitch self-triggered USVs were higher in EGF model rats in both age groups, although this group difference was eliminated by their risperidone treatment. Unlike conventional negative USVs of rats, however, the present low pitch self-triggered USVs had short durations of 10–30 ms. These results suggest the potential that self-triggered vocalization might serve as a translatable pathological trait of schizophrenia to animal models.
... "Increased IL6, a proinflammatory mediator is produced predominantly by macrophages and monocytes. Increased plasma levels of IL6 associated with schizophrenia are confirmed by several metaanalyses" (Potvin et al., 2008); [15,14]. "It has been demonstrated that both first episode and chronic schizophrenia patients showed a significant increased level of IL6 and TNFα in comparison to healthy control subjects" [16,17,18,19], suggesting IL6 may play a role in the pathogenesis of schizophrenia. ...
Schizophrenia is likely to be associated with immunological abnormalities. The aim of the study is to investigate the changes in NLR and some cytokines of patients with schizophrenia in Southeast, Nigeria. A total number 100 subjects were recruited for the study comprising 50 for the patients with Schizophrenia and 50 apparently healthy subjects both aged 25-60 years. Blood was collected from each subject and levels of cytokines were measured by Enzyme Linked Immunosorbent Assay WBC (x10 9 /L), Neutrophils and Lymphocyte were measured using manual counting method. Interleukin-6, TNF-α, WBC and Neutrophil values were significantly higher in Schizophrenic subjects than control subjects (p=0.00, 0.00, 0.00, and 0.001) respectively. Lymphocyte value was lower than control subjects (p<0.05). NLR was higher in patients with Schizophrenia than the control. In conclusion, there were significantly higher values in IL-6, WBC and Neutrophil levels of schizophrenic subjects when compared apparently healthy subjects.
... Inflammation is a plausible process that might link diverse environmental factors to genetic factors contributing to schizophrenia. Watanabe et al. (2010) have reviewed the evidence suggesting that inflammatory processes mediated by cytokines such as epidermal growth factor (EGF) and interleukins provide a common pathway linking genetic and environmental factors. Genome wide association studies have revealed evidence of multiple genetic variants implicated in immune mechanisms, most notably variants of immunity-related genes located on chromosome 6 in the vicinity of the Major Histocompatibility Locus, are associated with schizophrenia (Shi et al., 2009). ...
Current diagnostic criteria for schizophrenia place emphasis on delusions and hallucinations, whereas the classical descriptions of schizophrenia by Kraepelin and Bleuler emphasized disorganization and impoverishment of mental activity. Despite the availability of antipsychotic medication for treating delusions and hallucinations, many patients continue to experience persisting disability. Improving treatment requires a better understanding of the processes leading to persisting disability. We recently introduced the term classical schizophrenia to describe cases with disorganized and impoverished mental activity, cognitive impairment and predisposition to persisting disability. Recent evidence reveals that a polygenic score indicating risk for schizophrenia predicts severity of the features of classical schizophrenia: disorganization, and to a lesser extent, impoverishment of mental activity and cognitive impairment. Current understanding of brain function attributes a cardinal role to predictive coding: the process of generating models of the world that are successively updated in light of confirmation or contradiction by subsequent sensory information. It has been proposed that abnormalities of these predictive processes account for delusions and hallucinations. Here we examine the evidence provided by electrophysiology and fMRI indicating that imprecise predictive coding is the core pathological process in classical schizophrenia, accounting for disorganization, psychomotor poverty and cognitive impairment. Functional imaging reveals aberrant brain activity at network hubs engaged during encoding of predictions. We discuss the possibility that frequent prediction errors might promote excess release of the neurotransmitter, dopamine, thereby accounting for the occurrence of episodes of florid psychotic symptoms including delusions and hallucinations in classical schizophrenia. While the predictive coding hypotheses partially accounts for the time-course of classical schizophrenia, the overall body of evidence indicates that environmental factors also contribute. We discuss the evidence that chronic inflammation is a mechanism that might link diverse genetic and environmental etiological factors, and contribute to the proposed imprecision of predictive coding.
... Therefore, I sought to address whether our postnatal GxE model might show enhanced leukocyte infiltration into the developing brain. Given the possible association of schizophrenia with abnormal cytokine expression (reviewed in (Watanabe et al., 2010)), I investigated whether our GxE model also show abnormal cytokine secretion. Together, I have addressed these aims in the subventricular zone (SVZ) since it is in contact with the cerebrospinal fluid (CSF), the major source of substance exchange between the systemic circulation and the brain. ...
... Prenatal maternal infections are epidemiologically established risk factors for schizophrenia. Animal studies have demonstrated that exposure to perinatal inflammatory mediators (e.g., epidermal growth factor-EGF) induced schizophrenia-like cognitive and behavioral abnormalities after maturation (4,5). Indirect observations such as neuroimaging indicate that neuroinflammation occurs in the brain of patients in the acute phase of schizophrenia. ...
Recent studies have lent support to the possibility that inflammation is associated with the pathology of schizophrenia. In the study of measurement of inflammatory mediators, which are markers of inflammation, elevated inflammatory cytokine levels in the brain and blood have been reported in patients with schizophrenia. Several postmortem brain studies have also reported changes in the expression of inflammatory cytokines. However, it is not clear how these elevated inflammatory cytokines interact with other inflammatory mediators, and their association with the pathology of schizophrenia. We comprehensively investigated the expression of 30 inflammatory mediators in the superior temporal gyrus (STG) of 24 patients with schizophrenia and 26 controls using a multiplex method. Overall, inflammatory mediator expression in the STG was mostly unchanged. However, the expression of interleukin (IL)1-α and interferon-gamma-inducible protein (IP)-10 was decreased [IL-1α, median (IQR), 0.51 (0.37–0.70) vs. 0.87 (0.47–1.23), p = 0.01; IP-10, 13.99 (8.00–36.64) vs. 30.29 (10.23–134.73), p = 0.05], whereas that of IFN-α was increased [2.34 (1.84–4.48) vs. 1.94 (1.39–2.36), p = 0.04] in schizophrenia, although these alterations did not remain significant after multiple testing. Clustering based on inflammatory mediator expression pattern and analysis of upstream transcription factors using pathway analysis revealed that the suppression of IL-1α and IP-10 protein expression may be induced by regulation of a common upstream pathway. Neuroinflammation is important in understanding the biology of schizophrenia. While neuroimaging has been previously used, direct observation to determine the expression of inflammatory mediators is necessary. In this study, we identified protein changes, previously unreported, using comprehensive protein analysis in STG. These results provide insight into post-inflammatory alternation in chronic schizophrenia.
... In addition, it is demonstrated that transferring the gut microbiota from fecal microbiome of the SCZ patients to the normal or germ-free mice led to the SCZ-relevant behaviors similar to those in the SCZ rodent models . One of the eminent mechanisms involving in the pathogenesis of SCZ is immunoinflammatory response (Watanabe et al., 2010). ...
The human gastrointestinal tract hosts trillions of microorganisms that is called “gut microbiota.” The gut microbiota is involved in a wide variety of physiological features and functions of the body. Thus, it is not surprising that any damage to the gut microbiota is associated with disorders in different body systems. Probiotics, defined as living microorganisms with health benefits for the host, can support or restore the composition of the gut microbiota. Numerous investigations have proved a relationship between the gut microbiota with normal brain function as well as many brain diseases, in which cognitive dysfunction is a common clinical problem. On the other hand, increasing evidence suggests that the existence of a healthy gut microbiota is crucial for normal cognitive processing. In this regard, interplay of the gut microbiota and cognition has been under focus of recent researches. In the present paper, I review findings of the studies considering beneficial effects of either gut microbiota or probiotic bacteria on the brain cognitive function in the healthy and disease statuses.
... [2][3][4] Among various environmental factors, maternal infections or inflammation during the gestation draw our attention which can increase the risk of schizophrenia of the child. [5][6][7] Thus, we often employ the rodent offspring whose dams were challenged by viral and bacterial antigens as an animal model for maternal infections or inflammation, which result in various behavioral abnormalities relevant to schizophrenia endophenotypes. [8][9][10][11] Such associations warrant a discussion on the biological links between the maternal immune inflammatory history and the increased risk of the offspring developing this disease. ...
Genetic and environmental factors interact with each other to influence the risk of various psychiatric diseases; however, the intensity and nature of their interactions remain to be elucidated. We used a maternal infection model using polyinosinic-polycytidylic acid (Poly(I:C)) to determine the relationship between the maternal breeding environment and behavioral changes in the offspring. We purchased pregnant C57BL/6J mice from three breeders and administered Poly(I:C) (2 mg/kg) intravenously in their tail vein on gestation day 15. The offspring were raised to 8-12 weeks old and subjected to the acoustic startle tests to measure their startle response intensity, prepulse inhibition levels, and degree of the adaptation of the startle response. No statistical interaction between Poly(I:C) administration and sex was observed for prepulse inhibition; thus, male and female mice were analyzed together. The Poly(I:C) challenge significantly decreased prepulse inhibition levels of the offspring born to the pregnant dams from Breeder A but not those from the other breeders. However, there were no significant inter-breeder differences in Poly(I:C) effects on startle response and on startle adaptation. The rearing environment of mouse dams has a prominent impact on the Poly(I:C)-induced prepulse inhibition deficits in this maternal infection model.
... There are many overlapping and complementary theories and hypotheses about the causes of the disorder. Its development is probably due to the interaction of genetic and environmental factors that lead to neurostructural, neurochemical, and neurofunctional changes in the brain [2][3][4][5]. In 1992, Smith presented the macrophage (cytokine) theory of schizophrenia, according to which the disorder is based on immune-inflammatory reactions. ...
Schizophrenia is a heterogeneous disorder without a fully elucidated etiology and mechanisms. One likely explanation for the development of schizophrenia is low-grade inflammation, possibly caused by processes in the gastrointestinal tract related to gluten sensitivity. The aims of this study were to: (1) compare levels of markers of gluten sensitivity, inflammation and gut permeability, and (2) determine associations between gluten sensitivity, inflammation, and intestinal permeability in patients with first-episode/chronic (FS/CS) schizophrenia and healthy individuals (HC). The total sample comprised 162 individuals (52 FS; 50 CS, and 60 HC). The examination included clinical variables, nutritional assessment, and serum concentrations of: high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), soluble CD14 (sCD14), anti-Saccharomyces cerevisiae antibody (ASCA), antigliadin antibodies (AGA) IgA/IgG, antibodies against tissue transglutaminase 2 (anti-tTG) IgA, anti-deamidated gliadin peptides (anti-DGP) IgG. A significant difference between groups was found in sCD14, ASCA, hs-CRP, IL-6 and AGA IgA levels. AGA IgG/IgA levels were higher in the FS (11.54%; 30.77%) and CS (26%; 20%) groups compared to HC. The association between intestinal permeability and inflammation in the schizophrenic patients only was noted. The risk for developing schizophrenia was odds ratio (OR) = 4.35 (95% confidence interval (CI 1.23-15.39) for AGA IgA and 3.08 (95% CI 1.19-7.99) for positive AGA IgG. Inflammation and food hypersensitivity reactions initiated by increased intestinal permeability may contribute to the pathophysiology of schizophrenia. The immune response to gluten in FS differs from that found in CS.
... It has been suggested previously, that antipsychotics may be the cause of increased cytokine levels in SCZ patients (Watanabe, Someya, & Nawa, 2010), therefore, the increased levels of IL-18 observed in schizophrenics could simply be caused by the use of antipsychotic medication, however, this cannot be the case as this elevation in IL-18 levels has also been observed in antipsychotic naïve FEP patients who have never been exposed to antipsychotics. Furthermore, a study investigated the effect of antipsychotics in chronic SCZ patients and reported no significant difference in IL-18 levels due to antipsychotic type (typical vs atypical), dosage, duration and choice of antipsychotic drug (Xiu et al., 2012). ...
Aim:
To determine whether interleukin 18 (IL-18) is elevated in the blood of schizophrenia (SCZ) and first episode psychosis patients, as well as investigate whether this potential relationship is causal.
Method:
We conducted a systematic review and meta-analysis of IL-18 levels in the blood of SCZ patients, comprising of both chronic and first episode psychosis (FEP) cohorts. To investigate causality, we undertook the two-sample Mendelian randomization (MR) study.
Results:
A total of eight studies were included in our meta-analysis, our results did indeed show an association between elevated levels of IL-18 and SCZ compared to healthy controls (Z = 3.50, P = .0005). This association remained significant in subsequent subgroup analyses for chronic (Z = 3.15, P = .002) and achieved borderline significance in FEP (Z = 1.93, P = .05) SCZ. Our MR analysis failed to detect any causal relationship between IL-18 levels and SCZ.
Conclusion:
The results of our study demonstrate that even though IL-18 levels are elevated in SCZ patients, IL-18 levels do not seem to cause of the disorder itself. Our findings suggest that IL-18 may have utility as a biomarker of SCZ and aid in research into the early intervention of the disease.
... However, the factors and neurobiological mechanisms underlying AISLM remain poorly understood. In humans, viral or bacterial infections during pregnancy can delay the normal development of the central nervous system in the offspring (Watanabe et al., 2010;Diz-Chaves et al., 2013). Chronic inflammation due to maternal infection during pregnancy contributes to the activation of astroglia and microglia and subsequently an increase in the production of proinflammatory cytokines in the brains of offspring. ...
Age-associated impairment of spatial learning and memory (AISLM) presents substantial challenges to our health and society. Increasing evidence has indicated that embryonic exposure to inflammation accelerates the AISLM, and this can be attributable, at least partly, to changed synaptic plasticity associated with the activities of various proteins. However, it is still uncertain whether social psychological factors affect this AISLM and/or the expression of synaptic protein-associated genes. Synaptotagmin-1 (Syt1) and activity-regulated cytoskeleton-associated protein (Arc) are two synaptic proteins closely related to cognitive functions. In this study, pregnant CD-1 mice received daily intraperitoneal injections of lipopolysaccharide (LPS) (50 μg/kg) or normal saline at days 15–17 of gestation, and half of the offspring of each group were then subjected to stress for 28 days in adolescence. The Morris water maze (MWM) test was used to separately evaluate spatial learning and memory at 3 and 15 months of age, while western blotting and RNAscope assays were used to measure the protein and mRNA levels of Arc and Syt1 in the hippocampus. The results showed that, at 15 months of age, control mice had worse cognitive ability and higher protein and mRNA levels of Arc and Syt1 than their younger counterparts. Embryonic exposure to inflammation or exposure to stress in adolescence aggravated the AISLM, as well as the age-related increase in Arc and Syt1 expression. Moreover, the hippocampal protein and mRNA levels of Arc and Syt1 were significantly correlated with the performance in the learning and memory periods of the MWM test, especially in the mice that had suffered adverse insults in early life. Our findings indicated that prenatal exposure to inflammation or stress exposure in adolescence exacerbated the AISLM and age-related upregulation of Arc and Syt1 expression, and these effects were linked to cognitive impairments in CD-1 mice exposed to adverse factors in early life.
... According to the cytokine hypothesis of schizophrenia, we previously characterized the animal models for schizophrenia that were prepared by treating neonatal animals with the cytokines of ErbB receptor ligands (neuregulin-1 and epidermal growth factor (EGF)) (Nawa et al., 2000;Meyer et al., 2009;Patterson, 2009;Watanabe et al., 2010;Nawa et al., 2014). The EGF-or neuregulin-1-challenged mice and rats exhibit a variety of behavioral deficits relevant to schizophrenia including reduced prepulse inhibition, decreased social interaction, abnormal learning persistency, hypersensitivity to psychostimulants, and antipsychotic responses (Futamura et al., 2003;Mizuno et al., 2004;Kato et al., 2011;Sotoyama et al., 2011;Nawa et al., 2014). ...
Schizophrenia in humans typically develops during and after adolescence; however, the biological underpinning for the specificity of this onset time window remains to be determined. In the present study, we investigated this knowledge gap using our own animal model for schizophrenia; rodents and monkeys challenged with a cytokine, epidermal growth factor (EGF), as neonates exhibit various behavioral and cognitive abnormalities at the post-pubertal stage. We used the EGF-challenged mice as an animal model for schizophrenia to evaluate the electrophysiological impact of this modeling on nigral dopamine neurons before and after puberty. In vivo single unit recording revealed that the burst firing of putative dopamine neurons in substantia nigra pars compacta was significantly higher in the post-pubertal stage of the EGF model than in that of control mice; in contrast, this difference was not observed in the pre-pubertal stage. The increase in burst firing was accompanied by a decline in Ca²⁺-activated K⁺ (ISK) currents, which influence the firing pattern of dopamine neurons. In vivo local application of the SK channel blocker apamin (80 μM) to the substantia nigra was less effective at increasing burst firing in the EGF model than in control mice, suggesting the pathologic role of the ISK decrease in this model. Thus, these results suggest that the aberrant post-pubertal hyperactivity of midbrain dopaminergic neurons is associated with the temporal specificity of the behavioral deficit of this model, and support the hypothesis that this aberration could be implicated in the adolescent onset of schizophrenia.
... Different environmental factors and inflammatory immune processes have been shown to be involved in the etiology and pathology of schizophrenia. [4] There is evidence that cytokine elevation plays an important role in the pathogenesis of schizophrenia and is closely related to its etiology and pathogenesis. Interleukin-6 (IL-6), a major cytokine, plays several important roles in the central nervous system (CNS), such as regulating brain development and synaptic plasticity, and is also related to sleep and stress. ...
Background:
To evaluate the association between risperidone use and interleukin-6 (IL-6) levels by conducting a meta-analysis of controlled before-and-after studies.
Methods:
Studies were identified through a systematic search of PubMed and Embase. The mean and standardized differences were extracted to calculate the standardized mean differences. IL-6 levels were compared in patients with schizophrenia before and after risperidone treatment.
Results:
Ten studies were included in the final meta-analysis. The primary findings from our study suggest that there was a significant decrease in serum IL-6 levels after risperidone treatment (P = .021). A subgroup analysis revealed the sources of heterogeneity. The sensitivity analysis indicated that the results were stable, and no publication bias was observed.
Conclusions:
The present meta-analysis provides evidence that risperidone can significantly reduce IL-6 levels in schizophrenia. IL-6 is a potential biomarker of the pathophysiology and clinical processes of schizophrenia.
... From this standpoint, psychotic episodes in schizophrenia coincide with inflammatory mechanisms linked to the hypothalamic-pituitary stress-inflammatory pathways. This eventually leads to microglial and astrocyte activation [16,17]. Interestingly, the latter is also associated with the activation of the kynurenine pathway and increased the production of kynurenic acid (KYNA) in the cerebrospinal fluid (CSF) [18,19]. ...
Background:
In the last decade, there has been growing evidence that an interaction exists between inflammation and the kynurenine pathway in schizophrenia. Additionally, many authors found microglial activation in cases of schizophrenia due to inflammatory mechanisms related mostly to an increase of pro-inflammatory cytokines. In order to gain new insights into the pathophysiology of schizophrenia, it is important to incorporate the latest published evidence concerning inflammatory mechanisms and kynurenine metabolism. This systematic review aims to collect reliable recent findings within the last decade supporting such a theory.
Methods:
A structured search of electronic databases was conducted for publications between 2008 and 2018 to identify eligible studies investigating patients with schizophrenia/psychosis and the relationship between inflammation and kynurenine pathway. Applicable studies were systematically scored using the NIH Quality Assessment Tools. Two researchers independently extracted data on diagnosis (psychosis/schizophrenia), inflammation, and kynurenine/tryptophan metabolites.
Results:
Ten eligible articles were identified where seven studies assessed blood samples and three assessed cerebrospinal fluid in schizophrenic patients. Of these articles: Four investigated the relationship between immunoglobulins and the kynurenine pathway and found correlations between IgA-mediated responses and levels of tryptophan metabolites (i.e., kynurenine pathway).Five examined the correlation between cytokines and kynurenine metabolites where three showed a relationship between elevated IL-6, TNF-α concentrations, and the kynurenine pathway.Only one study discovered correlations between IL-8 and the kynurenine pathway.Two studies showed correlations with lower concentrations of IL-4 and the kynurenine pathway.Moreover, this systematic review did not find a significant correlation between CRP (n = 1 study), IFN-γ (n = 3 studies), and the kynurenine pathway in schizophrenia.
Interpretation:
These results emphasize how different inflammatory markers can unbalance the tryptophan/kynurenine pathway in schizophrenia. Several tryptophan/kynurenine pathway metabolites are produced which can, in turn, underlie different psychotic and cognitive symptoms via neurotransmission modulation. However, due to heterogeneity and the shortage of eligible articles, they do not robustly converge to the same findings. Hence, we recommend further studies with larger sample sizes to elucidate the possible interactions between the various markers, their blood vs. CSF ratios, and their correlation with schizophrenia symptoms.
... A possible explanation for these associations is that autoimmune inflammatory responses may increase the permeability of the blood-brain barrier and render the brain vulnerable to proinflammatory substances such as cytokines. 35 Therefore, immune components such as cytokines may increase the risk of schizophrenia in vulnerable individuals with asthma or COPD. Future studies should explore the complex mechanisms underlying the autoimmune process are involved in the development of schizophrenia. ...
Some physical illnesses are potentially associated with the development of schizophrenia. However, few studies have investigated these associations. Here, we examined physical illnesses and medical utilization patterns existing before patients received a diagnosis of schizophrenia. We enrolled a large representative cohort of the general population in Taiwan (N = 1 000 000) and identified 1969 young patients with a new diagnosis of schizophrenia from January 1, 2000 to December 31, 2013. We conducted a nested case-control study based on risk-set sampling. Each case was age-matched and sex-matched with 4 controls selected from the general population. The case and control groups were compared on the basis of various clinical characteristics. Conditional logistic regression was used to estimate the magnitude of risk associated with newly diagnosed schizophrenia. Within the 1 year before the schizophrenia diagnosis, the cases were most likely to visit the psychiatry department, followed by internal medicine and family medicine departments. According to multivariate analysis, compared with the controls, the cases had substantially higher risk of physical conditions in the prodromal phase, including hypertension (adjusted risk ratio [aRR] = 1.93, P = .001), other forms of heart disease (aRR = 2.07, P < .001), cerebrovascular diseases (aRR = 2.96, P = .001), chronic obstructive pulmonary disease (aRR = 1.50, P = .005), asthma (aRR = 1.76, P = .003), and irritable bowel syndrome (aRR = 2.00, P < .001). A wide range of psychiatric diseases and concomitant use of medications were significantly associated with schizophrenia development. In conclusion, several physical illnesses were identified to be associated with schizophrenia development, indicating that people with these illnesses could be vulnerable to schizophrenia.
... Interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α are a group of proinflammatory cytokines which have been indulged as a cardinal axis of a common pathway of AIS incidence and schizophrenia liability factors. Its production and signaling are intimately regulated by a various genes that may be accused for schizophrenia [18]. Oxidative stress has hazardous damaging effects on different cellular components and causes DNA damage with subsequent formation of 8-hydroxy-2' -deoxyguanosine (8-OHdG) that has been largely used as a biomarker for oxidative stress DNA damage [19]. ...
... The contributions of behavioural research on animals in the field of psychology are undisputable and are believed to have laid the foundation for the [5] treatment of phobias, drug addiction and anxiety disorders. Furthermore, animal research has facilitated the study of the neural basis for schizophrenia, retrograde amnesia, depression and a wide [6] range of other psychological phenomenon. It is due to these reasons that the American Association for the Advancement of Science (1990) stated that "the use of animals has been and continues to be essential in applied research with direct clinical applications in humans and [7] animals". ...
Background: Psychology courses and psychology students have very poor understanding of animal research and the ethical issues involved in animal research. This is despite the fact that animal research plays a vital role in behavioural
research. The study was aimed to survey the attitudes of psychology students towards animal research.
Methodology: A total of 202 undergraduate students in the final year of their undergraduate studies from various colleges of Mumbai were administered a semi-structured questionnaire on attitudes towards animal research. The questionnaire was validated by three senior researchers and was specially designed for the study. The data was collected and analysed using descriptive statistics and percentages.
Results: Only 50 students (24.75%) had ever visited animal house/ animal laboratory in the past and only 29 (14.36%) of them had actual experience of handling animals mainly in form of dissection studies on rats and cockroaches. Majority of them believed that animal research had no bearing on problems concerning humans (43.6%, n = 88) and 27.7% (n=56) of them were of neutral opinion. Almost 84% (n=168) of them were concerned of pain and suffering animals would have undergoing research. 90% students voted in favour of stringent ethical guidelines for animal research.
Conclusion: Animal research awareness is poor in undergraduate psychology students and there is a need to incorporate the same in their curriculum to help foster better understanding of animal research and its long term implications.
... Cluster labels are ranked according to P -values. If applicable, examples of biological processes are provided for each cluster (See Table S2 flammatory responses), perhaps as a result of infection [25,38,55,88]. The subsequent immune response interfere with normal neurodevelopment, leading to atypical synaptic connectivity. ...
Background
There is growing recognition that connectome architecture shapes cortical and sub-cortical grey matter atrophy across a spectrum of neurological and psychiatric diseases. Whether connectivity contributes to tissue volume loss in schizophrenia in the same manner remains unknown.
Methods
Here we relate tissue volume loss in patients with schizophrenia to patterns of structural and functional connectivity. Grey matter deformation was estimated in a sample of N = 133 individuals with chronic schizophrenia (48 female, 34.7 ± 12.9 years) and N = 113 controls (64 female, 23.5 ± 8.4 years). Deformation-based morphometry (DBM) was used to estimate cortical and subcortical grey matter deformation from T1-weighted MR images. Structural and functional connectivity patterns were derived from an independent sample of N = 70 healthy participants using diffusion spectrum imaging and resting-state functional MRI.
Results
We find that regional deformation is correlated with the deformation of structurally- and functionally-connected neighbours. Distributed deformation patterns are circumscribed by specific functional systems (the ventral attention network) and cytoarchitectonic classes (limbic class), with an epicenter in the anterior cingulate cortex.
Conclusions
Altogether, the present study demonstrates that brain tissue volume loss in schizophrenia is conditioned by structural and functional connectivity, accounting for 25-35% of regional variance in deformation.
Schizophrenia is a chronic, debilitating disorder with diverse symptomatology, including disorganised cognition and behaviour. Despite considerable research effort, we have only a limited understanding of the underlying brain dysfunction. A significant proportion of individuals with schizophrenia exhibit high levels of inflammation, and inflammation associated with maternal immune system activation is a risk factor for the disorder. In this review, we outline the potential role of inflammation in the disorder, with a particular focus on how cytokine release might affect the development and function of GABAergic interneurons. One consequence of this change in inhibitory control is a disruption in oscillatory processes in the brain. These changes disrupt the spatial and temporal synchrony of neural activity in the brain, which, by disturbing representations of time and space, may underlie some of the disorganisation symptoms observed in the disorder.
Interleukin-33 (IL-33) is a nuclear factor and member of the IL-1 cytokine family. IL-33 is mainly expressed by epithelial and endothelial cells and exerts its function through interaction with various immune cells, and binding to its receptor can form the IL-33/Suppression of tumorigenicity 2 (ST2) signaling pathway. While most cytokines are actively synthesized within cells, IL-33 is produced passively in response to tissue damage or cell necrosis, indicating its role as a signaling molecule following cellular infection, stress, or trauma. IL-33/ST2 signaling pathway has been proved to play diverse role in the pathological process of central nervous system disorders, cancer, fibrosis, autoimmune diseases, etc. Although research on the IL-33/ST2 signaling pathway has deepened recently, relevant treatment strategies have been proposed, and even targeted drugs are in the preclinical stage; further research on the effect of the IL-33/ST2 signaling pathway in different diseases is still necessary, to provide a clearer understanding of the different roles of IL-33/ST2 in disease progression and to develop new drugs and treatment strategies. Because IL-33/ST2 plays an important role in the occurrence and progression of diseases, the study of therapeutic drugs targeting this pathway is also necessary. This review focused on recent studies on the positive or negative role of IL-33/ST2 in different diseases, as well as the current related drugs targeting IL-33/ST2 in the preclinical and clinical stage. The mechanism of IL-33/ST2 in different diseases and its mediating effect on different immune cells have been summarized, as well as the antibody drugs targeting IL-33 or ST2, natural compounds with a mediating effect, and small molecule substances targeting relative pathway. We aim to provide new ideas and treatment strategies for IL-33/ST2-related drugs to treat different diseases.
In recent times, advances in the field of metabolomics have shed greater light on the role of metabolic disturbances in neuropsychiatric conditions. The following review explores the role of ketone bodies and ketosis in both the diagnosis and treatment of three major psychiatric disorders: major depressive disorder, anxiety disorders, and schizophrenia. Distinction is made between the potential therapeutic effects of the ketogenic diet and exogenous ketone preparations, as exogenous ketones in particular offer a standardized, reproducible manner for inducing ketosis. Compelling associations between symptoms of mental distress and dysregulation in central nervous system ketone metabolism have been demonstrated in preclinical studies with putative neuroprotective effects of ketone bodies being elucidated, including effects on inflammasomes and the promotion of neurogenesis in the central nervous system. Despite emerging pre-clinical data, clinical research on ketone body effectiveness as a treatment option for psychiatric disorders remains lacking. This gap in understanding warrants further investigating, especially considering that safe and acceptable ways of inducing ketosis are readily available.
Introduction
The ability to separate similar experiences into differentiated representations is proposed to be based on a computational process called pattern separation, and it is one of the key characteristics of episodic memory. Although pattern separation has been mainly studied in the dentate gyrus of the hippocampus, this cognitive function if thought to take place also in other regions of the brain. The perirhinal cortex is important for the acquisition and storage of object memories, and in particular for object memory differentiation. The present study was devoted to investigating the importance of the cellular mechanism of endocytosis for object memory differentiation in the perirhinal cortex and its association with brain-derived neurotrophic factor, which was previously shown to be critical for the pattern separation mechanism in this structure.
Methods
We used a modified version of the object recognition memory task and intracerebral delivery of a peptide (Tat-P4) into the perirhinal cortex to block endocytosis.
Results
We found that endocytosis is necessary for pattern separation in the perirhinal cortex. We also provide evidence from a molecular disconnection experiment that BDNF and endocytosis-related mechanisms interact for memory discrimination in both male and female rats.
Discussion
Our experiments suggest that BDNF and endocytosis are essential for consolidation of separate object memories and a part of a time-restricted, protein synthesis-dependent mechanism of memory stabilization in Prh during storage of object representations.
Background
Oxidative stress (OS) and neuroinflammatory pathways play an important role in the pathophysiology of schizophrenia. The present study investigated the relationship between OS, inflammatory cytokines, and clinical features in male patients with treatment-resistant schizophrenia (TRS).
Method
We measured plasma OS parameters, including manganese-superoxide dismutase (Mn-SOD), copper/zinc-containing SOD (CuZn-SOD), total-SOD (T-SOD), malondialdehyde (MDA), catalase (CAT), and glutathione peroxidase (GSH-Px); and serum inflammatory cytokines, including interleukin (IL)-1α, IL-6, tumor necrosis factor-alpha (TNF-α), and interferon (IFN)-γ, from 80 male patients with chronic schizophrenia (31 had TRS and 49 had chronic stable schizophrenia (CSS)), and 42 healthy controls. The severity of psychotic symptoms was evaluated using the Positive and Negative Syndrome Scale (PANSS).
Results
Compared with healthy controls, plasma Mn-SOD, CuZn-SOD, T-SOD, GSH-Px, and MDA levels were significantly lower, while CAT and serum IL-6 levels were higher in both TRS and CSS male patients (all P < 0.05). Significant differences in the activities of CAT (F = 6.068, P = 0.016) and IL-6 levels (F = 6.876, P = 0.011) were observed between TRS and CSS male patients after analysis of covariance. Moreover, a significant positive correlation was found between IL-6 levels and PANSS general psychopathology subscores (r = 0.485, P = 0.006) and between CAT activity and PANSS total scores (r = 0.409, P = 0.022) in TRS male patients. CAT and IL-6 levels were predictors for TRS. Additionally, in chronic schizophrenia patients, a significant positive correlation was observed between IL-6 and GSH-Px (r = 0.292, P = 0.012), and the interaction effect of IL-6 and GSH-Px was positively associated with PANSS general psychopathology scores (r = 0.287, P = 0.014).
Conclusion
This preliminary study indicated that variations in OS and inflammatory cytokines may be involved in psychopathology for patients with chronic schizophrenia, especially in male patients with TRS.
For the past 40 years, our team has conducted a unique program of research investigating the prenatal risks for schizophrenia and related adult psychiatric disorders. The New England Family Study is a long-term prospective cohort study of over 16,000 individuals followed from the prenatal period for over 50 years. This chapter summarizes several major phases and findings from this work, highlighting recent results on maternal prenatal bacterial infections and brain imaging. Implications regarding the causes and potential prevention of major psychotic disorders are discussed.
Schizophrenia is a chronic, debilitating disorder with diverse symptomatology, including disorganized cognition and behavior. Despite considerable research effort, we have only a limited understanding of the underlying brain dysfunction. In this article, we review the potential role of oscillatory circuits in the disorder with a particular focus on the hippocampus, a region that encodes sequential information across time and space, as well as the frontal cortex. Several mechanistic explanations of schizophrenia propose that a loss of oscillatory synchrony between and within these brain regions may underlie some of the symptoms of the disorder. We describe how these oscillations are affected in several animal models of schizophrenia, including models of genetic risk, maternal immune activation (MIA) models, and models of NMDA receptor hypofunction. We then critically discuss the evidence for disorganized oscillatory activity in these models, with a focus on gamma, sharp wave ripple, and theta activity, including the role of cross-frequency coupling as a synchronizing mechanism. Finally, we focus on phase precession, which is an oscillatory phenomenon whereby individual hippocampal place cells systematically advance their firing phase against the background theta oscillation. Phase precession is important because it allows sequential experience to be compressed into a single 120 ms theta cycle (known as a ‘theta sequence’). This time window is appropriate for the induction of synaptic plasticity. We describe how disruption of phase precession could disorganize sequential processing, and thereby disrupt the ordered storage of information. A similar dysfunction in schizophrenia may contribute to cognitive symptoms, including deficits in episodic memory, working memory, and future planning.
Suicide is a multifaceted phenomenon, related to an everlasting interconnection between biological, psychosocial, sociological, philosophical, and cultural aspects of human life. Immune system, which is constantly responding to changing environments and changing in response to them, seems to play a major role in this interaction. Multiple studies have reported increased risk of suicidal behaviours after or during inflammatory conditions. Individuals that engage in suicidal behaviours also have increased concentrations of inflammatory markers, such as interleukins 1β and 6, tumour necrosis factor α, and C-reactive protein, both in blood and the central nervous system (CNS). Stress, which is frequently mentioned among the major risk factors for suicidal behaviours, is also associated with a wide immune system dysregulation, entailing glucocorticoid system disruption and a low-grade inflammation. Mechanisms connecting systemic inflammation and CNS changes include damage to blood-brain barrier and interoceptive alterations, both resulting in changes in the communication between the periphery and the brain. Meanwhile, in CNS, pro-inflammatory cytokines may activate microglia causing a shift in tryptophan metabolism, preferentially generating cellular energy and toxic by-products of kynurenine pathway rather than serotonin. These changes in brain homeostasis lead to anatomical and functional brain alterations, most notably prefrontal cortex and insula, engendering maladaptive behavioural phenotypes, such as anhedonia and impulsivity that may mediate the association between inflammation and suicide. This chapter will provide a condensed overview of this complex association between inflammation and suicidal behaviours, presenting major findings in this area and explaining key pathways linking them.
Given the importance of understanding the role of neuroinflammation in psychiatric illness, including its emergence and progression, it is of practical value to explore the available tools that noninvasively index neuroinflammatory markers in vivo. Various aspects of neuroinflammation can be probed by magnetic resonance imaging (MRI) measures. These aspects include water content accumulation (T2-weighted anatomical MRI, magnetization transfer imaging and diffusion MRI); blood–brain barrier dysfunction and cellular infiltration (contrast-enhanced anatomical MRI); and molecular/metabolic signatures of neuroinflammation (magnetic resonance spectroscopy). This chapter provides a nontechnical overview of these MRI measures, which have been applied to estimate putative neuroinflammatory processes in psychiatric illness.
Schizophrenia (SZ) is a common, potentially debilitating disorder. Over 70% of risk for SZ at the population level is attributable to genetic factors. Large-scale genome-wide association studies (GWAS) have revealed risk attributable to over 170 genomic loci, with varied effect sizes. Statistically, the most significant risk locus maps to the major histocompatibility complex (MHC) region on chromosome 6 (odds ratio ~1.28). One of the associated MHC loci involved the complement C4 gene. There is population-wide variation in C4 gene copy number, and SZ risk rises with the number of C4 genes that an individual’s genome encodes. C4 is a component of an immunologic defense mechanism that predates antibody-based adaptive immunity. In mammals, complement proteins also participate in neurodevelopment. Based on rodent model studies, it has been proposed that the C4-related risk for SZ could be explained by aberrant synaptic pruning—a developmental process also implicated in SZ risk. We review the synaptic pruning hypothesis and propose additional mechanisms to explain the C4-SZ link, including disruption in classical immunologic processes and changes in human endogenous retroviral sequences associated with C4. The evidence supporting these hypotheses is discussed, and empirical investigations are proposed.
BACKGROUND: Schizophrenia is a mental disorder characterized by positive symptoms, negative, and cognitive deficits. Polymorphism of −174G/C interleukin-6 position of the promoter has been described as one of polymorphism that believes have association with schizophrenia and Batak people have a philosophy of life, principles, and at the same time as a structure and system in society called Dalihan na Tolu. This Dalihan na Tolu has a role in the Batak customary marriage laws that cannot be separated during a customary marriage ceremony according to the traditions of the Batak people. This system causes most Batak people to marry each other so that the purity of the population is maintained and can be applied according to Hardy-Weinberg Equilibrium. AIM: Hence, we looked for association in the polymorphism of −174G/C interleukin-6 between people with schizophrenia of the Bataknese population and healthy controls. METHODS: We conducted a cross-sectional study that included 75 people with schizophrenia in the Bataknese population and 75 healthy controls with the same ethnic group. The alleles and genotypes polymorphisms were compared between people with schizophrenia in the Bataknese population and healthy controls and were tested statistically using Chi-square. RESULTS: Frequency of appearance of allele and genotype of −174G/C polymorphism found that there were significant differences in both alleles and genotypes between groups of people with schizophrenia and healthy control groups (p < 0.001) and −174G/C polymorphisms were risk factors for schizophrenia statistically in the Bataknese population (Odds Ratio >1). CONCLUSIONS: We report an association of −174G/C polymorphism and schizophrenia in Bataknese population and polymorphism of −174G/C may be one of the risk factors for schizophrenia in the Bataknese population.
Genetic and environmental factors interact with each other to influence the risk of various psychiatric diseases; however, the intensity and nature of their interactions remain to be elucidated. We established a maternal infection model using polyinosinic-polycytidylic acid (Poly(I:C)) to determine the relationship between the maternal breeding environment and behavioral changes in the offspring. We purchased pregnant C57BL/6J mice from three breeders and administered Poly(I:C) (2 mg/kg) intravenously in their tail vein on gestation day 15. The offspring were raised to 8-12 weeks old and subjected to the acoustic startle tests to compare their startle response intensity, prepulse inhibition levels, and degree of the adaptation of the startle response. No statistical interaction between Poly(I:C) administration and sex was observed for prepulse inhibition; thus, male and female mice were analyzed together. There was a statistical interaction between the breeder origin of offspring and prepulse inhibition; the Poly(I:C) challenge significantly decreased prepulse inhibition levels of the offspring born to the pregnant dams from Breeder A but not those from the other breeders. However, we failed to detect significant inter-breeder differences in Poly(I:C) effects on startle response and on startle adaptation with the given number of mice examined. The rearing environment of mouse dams has a prominent effect on the Poly(I:C)-induced prepulse inhibition deficits in this maternal immune activation model.
Schizophrenia (SZ) is a chronic debilitating disease. Subjects with SZ have significant shorter life expectancy. Growing evidence suggests that a process of pathological accelerated aging occurs in SZ, leading to early development of severe clinical diseases and worse morbimortality. Furthermore, unaffected relatives can share certain endophenotypes with subjects with SZ. We aim to characterize accelerated aging as a possible endophenotype of schizophrenia by using a machine learning (ML) model of peripheral biomarkers to accurately differentiate subjects with SZ (n= 35), their unaffected siblings (SB, n= 36) and healthy controls (HC, n = 47). We used a random forest algorithm that included biomarkers related to aging: eotaxins CCL-11 and CCL-24; the oxidative stress markers thiobarbituric acid-reactive substances (TBARS), protein carbonyl content (PCC), glutathione peroxidase (GPx); and telomere length (TL). The ML algorithm of biomarkers was able to distinguish individuals with SZ from HC with prediction accuracy of 79.7%, SZ from SB with 62.5% accuracy and SB from HC with 75.5% accuracy. These results support the hypothesis that a pathological accelerated aging might occur in SZ, and this pathological aging could be an endophenotype of the disease, once this profile was also observed in SB, suggesting that SB might suffer from an accelerated aging in some level.
Viral infection in early pregnancy is a major cause of microcephaly. However, how distinct viruses impair human brain development remains poorly understood. Here we use human brain organoids to study the mechanisms underlying microcephaly caused by Zika virus (ZIKV) and herpes simplex virus (HSV-1). We find that both viruses efficiently replicate in brain organoids and attenuate their growth by causing cell death. However, transcriptional profiling reveals that ZIKV and HSV-1 elicit distinct cellular responses and that HSV-1 uniquely impairs neuroepithelial identity. Furthermore, we demonstrate that, although both viruses fail to potently induce the type I interferon system, the organoid defects caused by their infection can be rescued by distinct type I interferons. These phenotypes are not seen in 2D cultures, highlighting the superiority of brain organoids in modeling viral infections. These results uncover virus-specific mechanisms and complex cellular immune defenses associated with virus-induced microcephaly.
Background: Schizophrenia is a chronic mental disorder, characterized by acute exacerbation and remission phases. Immune system has a role in the pathophysiology of schizophrenia. High mobility group box-1 (HMGB-1) is a macrophage secreted protein activating immune cells to produce cytokines. The aim of this study was to evaluate HMGB-1 levels among patients with schizophrenia both in acute exacerbation and remission phases. Methods: Consecutive schizophrenia patients in acute exacerbation and remission phases were enrolled and compared with each other and with age-sex matched healthy subjects. Patients were assessed with the Scale for the Assessment of Positive Symptoms (SAPS), Scale for the Assessment of Negative Symptoms (SANS), Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression Scale (CGI). Results: Mean HMGB-1 levels were not significantly different in acute exacerbation phase versus remission phase schizophrenia patients (2139±564 pg/ml vs. 2326±471 pg/ml, p=0.335) and both were individually higher than the control group (1791±444 pg/ml, p=0.05 for acute exacerbation vs control, p=0.002 for remission vs control). In remission phase schizophrenic patients, HMGB-1 levels were positively correlated with Scale For The Assessment of Positive Symptoms (r=0.447, p=0.015) and BPRS (r=0.397, p=0.033) scores and HMGB-1 levels were independently associated with BPRS. Conclusion: Serum HMGB-1 levels were shown to be increased in patients with schizophrenia patients irrespective of phase and HMGB-1 levels were related to symptom severity according to psychiatric scales among patients in remission phase of schizophrenia.
There is a constant interest in blood-based protein biomarkers, which can help to improve diagnosis and treatment outcomes of multifactorial human pathologies. In this regard, proteomic studies usually employ plasma immunoaffinity fractionation to deplete the most abundant plasma proteins, due to the high dynamic concentration range of proteins. The depletion of high abundant proteins allows to obtain less abundant and, oftentimes, more interesting proteins. However, the removal of the fraction of the high abundant plasma proteins - the depletome - may co-elute many unintended proteins due to protein-protein interactions. Little data is available about the depletome and potential protein biomarkers may be lost during this process. To visualize and characterize these proteins, we analyzed the depletome of 20 plasma samples by shotgun mass spectrometry-based proteomics. Thus, using immunoaffinity depletion followed by 2-D liquid chromatography coupled to anion mobility-enhanced mass spectrometer, our analysis identified that over 100proteins are co-eluting with the high abundant fraction. These proteins play roles in several biological processes, such as receptor-mediated endocytosis, complement activation, and regulation of immune response. This study supports that investigating the depletome is important in the quest for biomarkers.
A large body of evidence indicates that both the altered cytokines that mediate the immune-inflammatory process and abnormal gray matter are associated with schizophrenia. Whether peripheral cytokines are related to cerebral structural abnormality remains unclear. Therefore, we aimed to investigate the association of peripheral cytokine levels with gray matter abnormalities at the whole brain level in schizophrenia. Forty-four outpatients with schizophrenia and 44 controls were recruited. The serum levels of interleukin-1 beta (IL-1β), IL-2, IL-6, IL-8, interferon-gamma (IFN-γ), transforming growth factor-beta (TGF-β), and IL-10 were measured using a quantitative chemiluminescence assay. High-resolution T1 weighted images were acquired from all subjects and processed using FreeSurfer software to obtain the cortical thickness, surface area, and cortical and subcortical gray matter volumes. The cytokines and cerebral structures were compared between patients and controls using analysis of covariance (ANCOVA). The association between the cytokines and whole cerebral structures was performed using stepwise linear regression. Patients had higher levels of IL-2, IL-6, IL-8, and IL-10 than controls. In patients, the IL-6 level was significantly associated with the cortical thickness in the left pars opercularis, right pars triangularis, left superior temporal gyrus, and right middle temporal gyrus, which showed structural differences between the two groups. Altered cytokine levels may be associated with particular but not all cortical abnormalities in schizophrenia, especially IL-6, which was significantly associated with the abnormal cortical thickness of the bilateral Broca's area and temporal gyrus, which provided neuroimaging evidence to support the relationship between peripheral cytokines and the cerebral cortex in schizophrenia.
Objective:
Since the inflammatory process has been implicated in the pathophysiology of psychiatric disorder, an important issue emerging is to assess the test-retest reliability of cytokine measurement in healthy individuals and patients with schizophrenia. The objective of the present study was to investigate the test-retest reliability of bead-based multiplex immunoassay technology (BMIT) for cytokine measurement by using a Bland-Altman plot (BAP).
Methods:
Twenty healthy individuals and twenty patients with schizophrenia were enrolled, and a 17-plex cytokine assay was used to measure inflammatory biomarkers at baseline and two weeks later. The test-retest reliability was examined by BAP, 95% limits of agreement (LOA), intraclass correlation coefficient (ICC), and coefficient of repeatability (CoR).
Results:
In the healthy controls, only interleukin (IL)-2, IL-13, IL-10, IL-17, and macrophage inflammatory protein-1β showed excellent ICC. The BAP with 95% LOA determined that 13 cytokines showed acceptable 95% LOA for a 2-week test-retest reliability, and only IL-1β, IL-12 and tumor necrosis factor (TNF)-α had significant test-retest bias. The CoR of cytokines varied significantly, ranging from 1.72 to 218.1. Compared with healthy controls, patients with schizophrenia showed significantly higher levels of IL-5, IL-13, and TNF-α and significantly lower levels of IL-4, IL-12, and interferon-gamma (IFN-γ). Of these six cytokines, IL-12 and TNF-α were considered suboptimal reliability.
Conclusion:
The findings from ICC and CoR implied that the test-retest reliability of BMIT for cytokine measurement were suboptimal. However, the BAP with 95% LOA confirmed that BMIT can reliably distinguish schizophrenia from healthy individuals in cytokine measurement, while significant within-subject variation and between-group overlapping were evident in cytokine expression.
Objectives
Dysregulation of peripheral immune responses has been detected in schizophrenic patients. Cytokines as the main regulators of immunological processes are also involved in brain development, which supports their putative role in the pathogenesis of schizophrenia.
Methods
In the present study, we compared transcript levels of interleukin (IL )‐1 , IL ‐2 , IL ‐6 , chemokine (C‐X‐C) ligand 8 (CXCL 8 ), transforming growth factor‐β (TGF ‐β ) and tumor necrosis factor‐α (TNF ‐α ) in the blood of 50 schizophrenic patients and 50 healthy participants.
Results
IL ‐6 transcript levels were significantly higher in male participants compared with female participants (P = 0.005). TGF ‐β transcript levels were significantly higher in patients compared with healthy participants (P = 0.001). In addition, there was a significant difference in its expression between cases and controls based on the sex of the participants. TNF ‐α transcript levels were higher in male schizophrenic patients (P = 0.007) and in female patients aged <50 years compared with the age‐ and sex‐matched healthy participants (P = 0.048). Transcript levels of other cytokines were not significantly different between cases and controls, which might be due to the effects of antipsychotic treatment in patients.
Conclusion
The present study provides further evidence for abnormal transcript levels of cytokines in schizophrenic patients, as well as distinct regulation of cytokine expression in women and men.
Increasing evidence has shown that the immune system is involved in the schizophrenia development, with alterations in immune cell reactivity being one possible factor contributing to its pathogenesis. The purpose of the study was to evaluate in vitro the capability of peripheral blood mononuclear cells (PBMCs) obtained from subjects with schizophrenia and controls to engage in spontaneous and phytohemagglutinin (PHA)-stimulated cytokine production. The concentrations of various cytokines (interleukin (IL)-1β, IL-17A, tumor necrosis factor (TNF), interferon (IFN)-γ and IL-10) in supernatants from cultured PBMCs were measured using the cytometric bead array. No significant differences in the spontaneous production of IL-1β, IL-17A, IFN-γ and IL-10 by PBMCs were detected between individuals with schizophrenia and controls. TNF synthesis by PBMCs was found to be lower among those with schizophrenia. In all subjects and controls, greater cytokine generation was associated with PBMCs treated with PHA compared with those that were not. The PBMCs from people with schizophrenia displayed considerably higher sensitivity to mitogen stimulation, as the production of IL-17A, TNF and IFN-γ was at least threefold of that observed in healthy subjects, which may be driven by antipsychotics taken by patients with schizophrenia. Correlation was observed between spontaneous production of IFN-γ and Positive and Negative Syndrome Scale G subscore (which measures the general symptoms of schizophrenia) and between PHA-stimulated synthesis of IL–17A and G subscore. Our data confirm that the immune system dysregulation may underlie schizophrenia pathophysiology. There is a potential possibility that immunological tests could be used as a diagnostic, therapeutic and side-effects biomarker for schizophrenia, but further studies are needed.
Little is known for certain about the genetics of schizophrenia. The advent of genomewide association has been widely anticipated as a promising means to identify reproducible DNA sequence variation associated with this important and debilitating disorder. A total of 738 cases with DSM-IV schizophrenia (all participants in the CATIE study) and 733 group-matched controls were genotyped for 492,900 single-nucleotide polymorphisms (SNPs) using the Affymetrix 500K two-chip genotyping platform plus a custom 164K fill-in chip. Following multiple quality control steps for both subjects and SNPs, logistic regression analyses were used to assess the evidence for association of all SNPs with schizophrenia. We identified a number of promising SNPs for follow-up studies, although no SNP or multimarker combination of SNPs achieved genomewide statistical significance. Although a few signals coincided with genomic regions previously implicated in schizophrenia, chance could not be excluded. These data do not provide evidence for the involvement of any genomic region with schizophrenia detectable with moderate sample size. However, a planned genomewide association study for response phenotypes and inclusion of individual phenotype and genotype data from this study in meta-analyses hold promise for eventual identification of susceptibility and protective variants.
Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%(1,2). We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.
Genetic linkage and association have implicated neuregulin-1 (NRG-1) as a schizophrenia susceptibility gene. We measured mRNA expression levels of the three major isoforms of NRG-1 (ie type I, type II, and type III) in the postmortem dorsolateral prefrontal cortex (DLPFC) from matched patients and controls using real-time quantitative RT-PCR. Expression levels of three internal controls-GAPDH, cyclophilin, and beta-actin-were unchanged in schizophrenia, and there were no changes in the absolute levels of the NRG-1 isoforms. However, type I expression normalized by GAPDH levels was significantly increased in schizophrenia DLPFC (by 23%) and positively correlated with antipsychotic medication dosage. Type II/type I and type II/type III ratios were significantly decreased (18 and 23% respectively). There was no effect on the NRG-1 mRNA levels of genotype at two SNPs previously associated with schizophrenia, suggesting that these alleles are not functionally responsible for abnormal NRG-1 expression patterns in patients. Subtle abnormalities in the expression patterns of NRG-1 mRNA isoforms in DLPFC may be associated with schizophrenia.
Many genes implicated in schizophrenia can be related to glutamatergic transmission and neuroplasticity, oligodendrocyte function, and other families clearly related to neurobiology and schizophrenia phenotypes. Others appear rather to be involved in the life cycles of the pathogens implicated in the disease. For example, aspartylglucosaminidase (AGA), PLA2, SIAT8B, GALNT7, or B3GAT1 metabolize chemical ligands to which the influenza virus, herpes simplex, cytomegalovirus (CMV), rubella, or Toxoplasma gondii bind. The epidermal growth factor receptor (EGR/EGFR) is used by the CMV to gain entry to cells, and a CMV gene codes for an interleukin (IL-10) mimic that binds the host cognate receptor, IL10R. The fibroblast growth factor receptor (FGFR1) is used by herpes simplex. KPNA3 and RANBP5 control the nuclear import of the influenza virus. Disrupted in schizophrenia 1 (DISC1) controls the microtubule network that is used by viruses as a route to the nucleus, while DTNBP1, MUTED, and BLOC1S3 regulate end
Neuregulin-1 (NRG1) is implicated in the etiology or pathology of schizophrenia, although its biological roles in this illness are not fully understood. Human midbrain dopaminergic neurons highly express NRG1 receptors (ErbB4). To test its neuropathological role in the neurodevelopmental hypothesis of schizophrenia, we administered type-1 NRG1 protein to neonatal mice and evaluated the immediate and subsequent effects on dopaminergic neurons and their associated behaviors. Peripheral NRG1 administration activated midbrain ErbB4 and elevated the expression, phosphorylation and enzyme activity of tyrosine hydroxylase (TH), which ultimately increased dopamine levels. The hyperdopaminergic state was sustained in the medial prefrontal cortex after puberty. There were marked increases in dopaminergic terminals and TH levels. In agreement, higher amounts of dopamine were released from this brain region of NRG1-treated mice following high potassium stimulation. Furthermore, NRG1-treated mice exhibited behavioral impairments in prepulse inhibition, latent inhibition, social behaviors and hypersensitivity to methamphetamine. However, there were no gross abnormalities in brain structures or other phenotypic features of neurons and glial cells. Collectively, our findings provide novel insights into neurotrophic contribution of NRG1 to dopaminergic maldevelopment and schizophrenia pathogenesis.
Maternal influenza during pregnancy is a controversial risk factor for schizophrenia in the child. We conducted a meta-analysis to examine whether birth during the 9-month period after the pandemic of 1957 was a risk factor for schizophrenia. Studies that compared the risk of schizophrenia among subjects born after the pandemic with that among those born in corresponding time periods in surrounding years were divided into those conducted in the United States, Europe, or Australia (type A studies, n = 8) and those from Japan, where the epidemic came in 2 waves (type B studies, n = 3). Other studies examined the risk among subjects born to mothers who were pregnant during the pandemic and reported having had influenza (type C studies, n = 2). Relative risks (RRs) were extracted or calculated for each month and/or trimester of possible exposure by 2 independent authors. All analyses were performed using a fixed-effects model. The weighted results of the type A studies did not indicate a significantly increased risk of schizophrenia among children exposed during any trimester or month of prenatal life. Not a single study found a significant first- or second-trimester effect. The mean weighted RR for subjects who were in their first, second, or third trimester of prenatal life during the pandemic (8 effect sizes) was 0.91 (95% confidence interval [CI]: 0.85-0.98), 1.00 (95% CI: 0.93-1.07), and 1.05 (95% CI: 0.98-1.12), respectively. The pooled results of the type B and type C studies were also negative. Given high infection rates during the pandemic (about 50%), these results do not support the maternal influenza hypothesis.
Molecular Psychiatry publishes work aimed at elucidating biological mechanisms underlying psychiatric disorders and their treatment
Recently, neurotrophic factors and cytokines have been shown to be associated in psychiatric disorders, such as schizophrenia, bipolar disorder, and depression. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF family, serves as a neurotrophic molecular and plays a significant role in the brain. We generated mice in which HB-EGF activity is disrupted specifically in the ventral forebrain. These knockout mice showed (a) behavioral abnormalities similar to those described in psychiatric disorders, which were ameliorated by typical or atypical antipsychotics, (b) altered dopamine and serotonin levels in the brain, (c) decreases in spine density in neurons of the prefrontal cortex, (d) reductions in the protein levels of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor and post-synaptic protein-95 (PSD-95), (e) decreases in the EGF receptor, and in the calcium/calmodulin-dependent protein kinase II (CaMK II) signal cascade. These results suggest the alterations affecting HB-EGF signaling could comprise a contributing factor in psychiatric disorder.
Activation of the inflammatory response system and varied levels of cytokines in acute schizophrenia have been suggested by recent studies. Psychopharmacologic agents can differentially effect cytokine production, which suggests that therapeutic function of neuroleptics may involve immunomodulation.
The present study was carried out to examine: (i) serum concentrations of interleukin (IL)-1β , soluble interleukin-2 receptor (sIL-2R), IL-6, IL-8 and tumour necrosis factor (TNF)- α in schizophrenic patients; (ii) their relation with psychopathological assessment; and (iii) the relation of the initial cytokine levels with responsiveness to risperidone therapy.
Thirty-four drug-free schizophrenic patients with acute exacerbation and 23 age- and gender-matched healthy controls were recruited for this study. Psychopathological assessments at admission and throughout risperidone treatment for 60 days were recorded. Serum cytokine concentrations were determined with chemilumunescence assays.
According to our results, serum IL-1β , sIL-2R, IL-6, IL-8 and TNF-α concentrations adjusted for age, gender, body mass index and smoking were no different in patients with schizophrenia and controls and among subtypes of schizophrenia. However, the initial TNF-α concentrations had a significant effect on Brief Psychiatric Rating Scale and Scale Assessment of Positive Symptoms scores. The initial cytokine concentrations of the patients responsive to risperidone were not significantly different from those of non-responsive patients.
The present study demonstrates that plasma levels of IL-1β , sIL-2R, IL-6, IL-8 and TNF-α adjusted for confounding factors are not altered in drug-free schizophrenic patients at acute exacerbation. We suggest that, if cytokine production is altered in schizophrenia, these alterations may not be detectable in systemic circulation. According to our results, the therapeutic effect of risperidone is not related to basal levels of the aforementioned cytokines. However, serum TNF-α may contribute to symptomatology in schizophrenia.
Neuregulin 1 (NRG1), a growth factor involved in neurodevelopment, myelination, neurotransmitter receptor expression, and synaptic plasticity, first joined the list of candidate genes for schizophrenia when a 7-marker haplotype at the 5' end of the gene (Hap(ICE)) was shown to be associated with the disorder in the Icelandic population. Since then, more genetic and functional evidence has emerged, which supports a role for NRG1 in the development of schizophrenia.
To determine the contribution of NRG1 to susceptibility for schizophrenia in a northern Swedish isolated population.
Detailed linkage disequilibrium (LD)-based patient-control association study. This is the first study to type and analyze the 7 Hap(ICE) markers and a set of 32 HapMap tagging single-nucleotide polymorphisms (SNPs) that represents variants with a minor allele frequency of at least 1% and fully characterizes the LD structure of the 5' part of NRG1.
Outpatient and inpatient hospitals.
A total of 486 unrelated patients with schizophrenia and 514 unrelated control individuals recruited from a northern Swedish isolated population.
Association between markers and disease.
Analysis of the Hap(ICE) markers showed the association of a 7-marker and 2-microsatellite haplotype, different from the haplotypes associated in the Icelandic population and overrepresented in northern Swedish control individuals. Subsequently, a more detailed analysis that included all 37 genotyped SNPs was performed by investigating haplotypic association, dependent and independent of LD block structure. We found significant association with 5 SNPs located in the second intron of NRG1 (.007 </= P </= .04). Also, 2-, 3-, and 4-SNP windows that comprise these SNPs were associated (P < 3 x 10(-4)). One protective haplotype (0% vs 1.8%; P <5 x 10(-5)) and 1 disease risk-causing haplotype (40.4% vs 34.9%, P = .02) were defined.
The NRG1 gene contributes to the susceptibility for schizophrenia in the northern Swedish population.
The etiology of schizophrenia remains unclear, while there has been a growing amount of evidence for the neuroinflammation and immunogenetics, which are characterized by an increased serum concentration of several pro-inflammatory cytokines. Despite the fact that microglia comprise only <10% of the total brain cells, microglia respond rapidly to even minor pathological changes in the brain and may contribute directly to the neuronal degeneration by producing various pro-inflammatory cytokines and free radicals. In many aspects, the neuropathology of schizophrenia has recently been reported to be closely associatedwith microglial activation. Previous studies have shown the inhibitory effects of some typical/atypical antipsychotics on the release of inflammatory cytokines and free radicals from activated microglia, both of which have recently been known to cause a decrease in neurogenesis as well as white matter abnormalities in the brains of patients with schizophrenia. The microglia hypothesis of schizophrenia may shed new light on the therapeutic strategy for schizophrenia.
Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5-1%, with high heritability (80-85%) and complex transmission. Recent studies implicate rare, large, high-penetrance copy number variants in some cases, but the genes or biological mechanisms that underlie susceptibility are not known. Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended major histocompatibility complex region on chromosome 6. We carried out a genome-wide association study of common SNPs in the Molecular Genetics of Schizophrenia (MGS) case-control sample, and then a meta-analysis of data from the MGS, International Schizophrenia Consortium and SGENE data sets. No MGS finding achieved genome-wide statistical significance. In the meta-analysis of European-ancestry subjects (8,008 cases, 19,077 controls), significant association with schizophrenia was observed in a region of linkage disequilibrium on chromosome 6p22.1 (P = 9.54 x 10(-9)). This region includes a histone gene cluster and several immunity-related genes--possibly implicating aetiological mechanisms involving chromatin modification, transcriptional regulation, autoimmunity and/or infection. These results demonstrate that common schizophrenia susceptibility alleles can be detected. The characterization of these signals will suggest important directions for research on susceptibility mechanisms.
Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.
We report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following up the top hits in four independent cohorts comprising 1,460 patients and 12,995 controls, all of European origin. We found no genome-wide significant associations, nor could we provide support for any previously reported candidate gene or genome-wide associations. We went on to examine CNVs using a subset of 1,013 cases and 1,084 controls of European ancestry, and a further set of 60 cases and 64 controls of African ancestry. We found that eight cases and zero controls carried deletions greater than 2 Mb, of which two, at 8p22 and 16p13.11-p12.4, are newly reported here. A further evaluation of 1,378 controls identified no deletions greater than 2 Mb, suggesting a high prior probability of disease involvement when such deletions are observed in cases. We also provide further evidence for some smaller, previously reported, schizophrenia-associated CNVs, such as those in NRXN1 and APBA2. We could not provide strong support for the hypothesis that schizophrenia patients have a significantly greater "load" of large (>100 kb), rare CNVs, nor could we find common CNVs that associate with schizophrenia. Finally, we did not provide support for the suggestion that schizophrenia-associated CNVs may preferentially disrupt genes in neurodevelopmental pathways. Collectively, these analyses provide the first integrated study of SNPs and CNVs in schizophrenia and support the emerging view that rare deleterious variants may be more important in schizophrenia predisposition than common polymorphisms. While our analyses do not suggest that implicated CNVs impinge on particular key pathways, we do support the contribution of specific genomic regions in schizophrenia, presumably due to recurrent mutation. On balance, these data suggest that very few schizophrenia patients share identical genomic causation, potentially complicating efforts to personalize treatment regimens.
Adult exposure to NMDA receptor antagonists, such as ketamine, produces psychosis in humans, and exacerbates symptoms in schizophrenic patients. We recently showed that ketamine activates the innate immune enzyme NADPH-oxidase in brain, and that the superoxide produced leads to dysfunction of a subset of fast-spiking inhibitory interneurons expressing the calcium-binding protein parvalbumin (PV). Here we show that neuronal production of interleukin-6 (IL-6) is necessary and sufficient for ketamine-mediated activation of NADPH-oxidase in brain. Removal of IL-6 in neuronal cultures by anti-IL-6 blocking antibodies, or in vivo by use of IL-6-deficient mice, prevented the increase in superoxide by ketamine and rescued the interneurons. Accumulating evidence suggests that schizophrenia patients suffer from diminished antioxidant defenses, and a recent clinical trial showed that enhancing these defenses may ameliorate symptoms of the disease. Our results showing that ketamine-induced IL-6 is responsible for the activation of NADPH-oxidase in brain suggest that reducing brain levels of this cytokine may protect the GABAergic phenotype of fast-spiking PV-interneurons and thus attenuate the propsychotic effects of ketamine.
we currently believe that by translating attentional theories into testable hypotheses, we will be able to advance our understanding of schizophrenic psychopathology
by using converging operations and new methodologies, we are now in a position to generate and test critical, operationally defined hypotheses
this approach allows us to dissect both the information processing chain of events and the underlying neurobiological mechanisms that are disordered in schizophrenia (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Maternal viral infection is known to increase the risk for schizophrenia and autism in the offspring. Using this observation in an animal model, we find that respiratory infection of pregnant mice (both BALB/c and C57BL/6 strains) with the human influenza virus yields offspring that display highly abnormal behavioral responses as adults. As in schizophrenia and autism, these offspring display deficits in prepulse inhibition (PPI) in the acoustic startle response. Compared with control mice, the infected mice also display striking responses to the acute administration of antipsychotic (clozapine and chlorpromazine) and psychomimetic (ketamine) drugs. Moreover, these mice are deficient in exploratory behavior in both open-field and novel-object tests, and they are deficient in social interaction. At least some of these behavioral changes likely are attributable to the maternal immune response itself. That is, maternal injection of the synthetic double-stranded RNA polyinosinic-polycytidylic acid causes a PPI deficit in the offspring in the absence of virus. Therefore, maternal viral infection has a profound effect on the behavior of adult offspring, probably via an effect of the maternal immune response on the fetus.
Neuropoietic cytokines are well known for their role in the control of neuronal, glial and immune responses to injury or disease. Since this discovery, it has emerged that several of these proteins are also involved in nervous system development, in particular in the regulation of neurogenesis and stem cell fate. Recent data indicate that these proteins have yet more functions, as key modulators of synaptic plasticity and of various behaviours. In addition, neuropoietic cytokines might be a factor in the aetiology of psychiatric disorders.
• Human and animal model studies of sensorimotor gating allow us to understand the functional significance of attentional abnormalities and monoaminergic alterations in patients with schizophrenic disorders. Clinically, schizophrenic patients report oversensitivity to sensory stimulation that theoretically correlates with stimulus overload and leads to cognitive fragmentation. Paradigms using cortical event-related potentials and the prepulse inhibition of startle responses show that schizophrenic patients also have impaired central nervous system inhibition (sensorimotor gating). Animal model studies demonstrate that increased systemic aminergic activity and increased nucleus accumbens dopamine tone causes sensorimotor gating failure, similar to that seen in schizophrenic patients. The time course of the observed schizophrenic and animal model deficits is compatible with the "temporal map" of monoaminergic neuron functions (ie, several hundred miliseconds). Studies of sensorimotor gating allow investigators to comment on the spatial and temporal mapping of neurons, trait and state deficits, and vulnerability factors in the schizophrenic spectrum of disorders. By translating attentional theories into testable hypotheses, the neurobiology of schizophrenic disorders becomes clearer.
Two-dimensional (2D) depth-averaged hydrodynamic model was applied to simulate flow field around a circular pier in clear water. A correction factor was included in the friction term to take account the effect of streamline curvature due to flow separation and vortex shedding. In this study, 2D model simulate not only the vortex shedding in the turbulence wake but also bed shear stress distribution. The simulated bed shear stress contours were close to experimental measurements and three-dimensional (3D) modeling results. Since 2D model is much simpler and requires significantly less computational time than three-dimensional model, these results demonstrated that an improved 2D model is a capable tool of simulating bed shear stress distribution around bridge piers. Research in enhancing and applying 2D model to simulating the initiation and development of local scour is still a challenging topic for hydraulic engineers.
A significant difference of plasma interleukin (IL)-1 alpha concentration was found between schizophrenic patients taking neuroleptic drugs in = 38) and those not taking them in = 14; P<0.02); KruskaI-Wallis analysis revealed a significant difference of plasma IL-6 concentration among the patients taking neuroleptic drugs, those not taking them, and healthy control subjects (H = 7.1, d.f. = 2, P< 0.05); also, there was a significant difference of plasma IL-6 concentration between the patients taking neuroleptlic drugs in = 32) and those not taking them in = 13; P< 0.01). No significant differences were found between the three groups in the concentrations of IL-1 beta, IL-2 and tumour necrosis factor(TNF)-alpha. The present results suggest that neuroleptic treatment may change IL-la and IL-6 production in schizophrenic patients.
Monocytes from different individuals show variable cytokine production in response to a variety of stimuli. We wished to determine the sets of conditions (cytokine combinations) that would enable us to demonstrate stable inter-individual differences in the production of IL-1α, IL-1β, IL-1Ra, IL-6 and tumour necrosis factor-alpha (TNF-α) by monocytes. We assessed the ability of a number of recombinant human cytokines (granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-γ), TNF-α, IL-4, IL-6, transforming growth factor-beta (TGF-β), IL-10 and IL-1Ra) to stimulate or inhibit the production of one or more of these monocyte products. GM-CSF was found to stimulate the production of all five of these cytokines in a highly reproducible manner. TNF-α also up-regulated production of IL-1α, IL-1β, IL-1Ra and IL-6 by monocytes, but the variability in the results of cells cultured from the same individuals on different occasions was greater. Other cytokines either stimulated production of only some of the five cytokine products tested, or stimulated the production of some cytokine products while inhibiting production of others. This was especially evident when cytokines were used in combination with GM-CSF: IFN-γ down-regulated production of IL-1Ra while up-regulating the production of IL-1α/β, IL-6 and TNF-α, while IL-4 had the exact opposite effect. Polymorphisms in regions of cytokine genes that affect transcription may account for some of the inter-individual variation in cytokine production. We have shown that a stable estimate of cytokine production phenotype can be obtained when monocytes collected on at least two separate occasions are stimulated by GM-CSF in vitro. We have looked for a relationship between IL-1 production and an 86-bp variable repeat polymorphism in intron 2 of the IL-1Ra gene. A less common allele of this polymorphism (allele 2) was associated with increased production of IL-1Ra protein, and also reduced production of IL-1α protein by monocytes.
The genes of the interleukin-1 (IL-1) complex code for three proteins: IL-1α, IL-1β and the IL-1 receptor antagonist (IL-1RA). Each of these genes is polymorphic and there is increasing evidence that certain alleles are associated with increased susceptibility to a given disease of inflammatory nature. In the IL-1β gene there are two base-exchange polymorphisms in positions −511 and +3953, and IL-1RA gene has a penta-allelic polymorphic site in intron 2 containing variable numbers of an 86-bp tandem repeat sequence. As the IL-1β/IL-1RA ratio may be critical in the regulation of inflammation, we examined whether there are allelic associations between these loci (thus suggesting co-ordinate regulation) and whether these have an effect on the in vitro production of IL-1β. We found that the IL-1RA allele 2 (IL1RN*2) is associated with the presence of allele 2 of the IL-1β gene (position −511) and with the absence of allele 2 of the IL-1β gene (position +3953). Mononuclear cells from carriers of allele 2 (position −511) and non-carriers of allele 2 (position +3953) had a slight, but non-significant, elevated capacity to produce IL-1βin vitro. However, IL-1RA allele 2 strongly increased in vitro production of IL-1β, regardless of the presence or absence of these alleles. Taken together, these data suggest that the known allelisms in the IL-1β gene are not major regulators of the in vitro IL-1β production, but the IL-1RA allele 2 (or an unknown allele strongly associated with it) has a decisive role.
Plasma levels of interleukin (IL)-1β and IL-6 were measured in 60 acutely hospitalized psychiatric patients and in 60 healthy controls by enzyme-linked immunosorbent assay (ELISA). Almost no IL-6 was detected in the plasma of the patients or controls. The mean level of IL-1β was found to be significantly higher in schizophrenic patients than in their corresponding controls (P=0.03). The acute schizophrenics, but not the group of chronic schizophrenics, contributed to this increase. No correlation with age, duration of illness or overt psychopathology was found. The neuroleptic medication did not prove to have a significant effect on the plasma IL-1β levels. There was no difference between non-psychotic affective disorder patients (N = 17) and the controls.
In the present study we searched for restriction fragment length polymorphisms (RFLP) in the human interleukin-1β (IL-lβ) gene and for correlations to monocyte (Mo) function in non-related healthy donors and insulin-dependent diabetic patients. We demonstrated a diallelic polymorphism with the restriction enzyme TaqI consisting of fragments of 9.4 kb and 13.4 kb. No differences in allele or genotype frequencies of this RFLP were observed between randomly selected controls and randomly selected patients with insulin-dependent diabetes mel-litus (IDDM). However, when analysing IDDM patients negative for HLA-DR3 and -DR4, our data demonstrate that the 13.4 kb allele is more frequent in this group compared to a matched control group. The functional impact of this RFLP was studied by analysing in vitro stimulated Mo IL-1β response. An IL-lβ allele dosage effect on secretory capacity was observed after LPS-stimulation: 13.4/13.4 kb homo-zygous individuals secreted significantly more IL-lβ than 9.4/13.4 kb heterozygous individuals, who secreted significantly more than 9.4/9.4 kb homozygous individuals. Analyses of supernatants from LPS-sti-mulated Mo cultures from individuals with each Taql IL-lβ genotype revealed no differences in the mouse thymocyte co-stimulatory assay when compared on a molar basis, indicating that the Taql polymorphism gave rise only to quantitative differences in expression levels and probably not to a mutant IL-lβ. We conclude that the 13.4 kb allele represents an IL-1β‘high-secretor’ phenotype, that the observed RFLP may be a genetic susceptibility marker for IDDM in non-DR3 and non-DR4 individuals and that high IL-1β secretory capacity may be a pathogenic factor for IDDM in these patients.
The genes in the IL-1 complex code for three proteins, IL-1α, IL-1β and the IL-1 receptor antagonist (IL-1Ra). The severity of a given infection is influenced by the balance between the levels of IL-1β, the major extracellular agonist, and that of IL-1Ra. In healthy individuals, IL-1Ra is readily detectable in plasma but IL-1β levels are usually undetectable. As there are polymorphisms in both of these genes, we have now analyzed whether there are allelic associations between these loci and whether these would have an influence on plasma IL-1Ra levels. In 200 healthy blood donors, the mean plasma IL-1Ra concentration was 681 pg/ml. The IL-1Ra allele 2 (IL1RN*2) had a clear influence on IL-1Ra levels: its carriers had higher levels than the non-carriers (745 ng/ml vs. 627 pg/ml, p < 0.05, t -test). As marker alleles for IL-1β we used two biallelic base-exchange polymorphisms (at positions − 511 and + 3953 relative to the transcriptional start site). The more rare allele of IL-1β − 511 (allele 2) was significantly associated with the presence of IL-1Ra allele 2, but in the case of the IL-1β + 3953, the more rare allele (allele 2) was less frequent in the carriers of the IL-1Ra allele 2. These IL-1β allelisms did not have a direct influence on plasma IL-1Ra levels, but the enhancing effect of IL-1Ra allele 2 on IL-1Ra plasma levels required the presence of the IL-1β − 511 allele 2 or absence of the IL-1β + 3953 allele 2. Taken together, these results indicate that the IL-1β gene participates in the regulation of IL-1Ra production in vivo and that the alleles of IL-1β and IL-1Ra which demonstrate this cooperative effect are often associated.
Background:
It has been postulated that autoimmune process may play a role in the pathogenesis of symptoms in some schizophrenic patients. Findings of altered interleukin (IL) regulation have been regarded as additional proof that schizophrenia has an autoimmunological background.
Methods:
Sixteen patients who fulfilled DSM-IV criteria for schizophrenia and who were drug free for at least six months and the same number of age- and sex-matched controls were recruited. The severity of symptoms in schizophrenia was assessed by BPRS. Phytohemagglutinin (PHA)-stimulated production and serum level of IL-1 beta, IL-2, and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA).
Results:
There was a significant decrease of IL-2 production (p < .01) in schizophrenic patients and a significant increase of IL-2 serum level (p < .01). No significant difference of IL-1 beta and IL-6 was found. Some patients and controls had measurable serum level of IL-1 beta and IL-6. No significant correlation between production and serum level of IL-1 beta, -2, -6 and age, duration of illness, and BPRS score in schizophrenics was found.
Conclusions:
This is the first study to describe a decrease of IL-2 production and increase of IL-2 serum level in non-Caucasian schizophrenic patients. These findings are further evidence that autoimmune process is present, regardless of ethnic origin, in some schizophrenic patients.
While genetic factors account for a significant proportion of liability to schizophrenia, a body of evidence attests to a significant environmental contribution. Understanding the mechanisms through which genetic and environmental factors coalesce in influencing schizophrenia is critical for elucidating the pathways underlying psychotic illness and for developing primary prevention strategies. Although obstetric complications (OCs) remain among the most well-documented environmental indicators of risk for schizophrenia, the pathogenic role they play in the etiology of schizophrenia continues to remain poorly understood. A question of major importance is do these factors result from a genetic diathesis to schizophrenia (as in gene-environment covariation), act additively or interactively with predisposing genes for the disorder in influencing disease risk, or independently cause disease onset? In this review, we evaluate 3 classes of OCs commonly related to schizophrenia including hypoxia-associated OCs, maternal infection during pregnancy, and maternal stress during pregnancy. In addition, we discuss several mechanisms by which OCs impact on genetically susceptible brain regions, increasing constitutional vulnerability to neuromaturational events and stressors later in life (ie, adolescence), which may in turn contribute to triggering psychosis.
The genes of the interleukin-1 (IL-1) complex code for three proteins: IL-1alpha, IL-1beta and the IL-1 receptor antagonist (IL-1RA). Each of these genes is polymorphic and there is increasing evidence that certain alleles are associated with increased susceptibility to a given disease of inflammatory nature. In the IL-1beta gene there are two base-exchange polymorphisms in positions -511 and +3953, and IL-1RA gene has a penta-allelic polymorphic site in intron 2 containing variable numbers of an 86-bp tandem repeat sequence. As the IL-1beta/IL-1RA ratio may be critical in the regulation of inflammation, we examined whether there are allelic associations between these loci (thus suggesting co-ordinate regulation) and whether these have an effect on the in vitro production of IL-1beta. We found that the IL-1RA allele 2 (IL1RN*2) is associated with the presence of allele 2 of the IL-1beta gene (position -511) and with the absence of allele 2 of the IL-1beta gene (position +3953). Mononuclear cells from carriers of allele 2 (position -511) and non-carriers of allele 2 (position +3953) had a slight, but non-significant, elevated capacity to produce IL-1beta in vitro. However, IL-1RA allele 2 strongly increased in vitro production of IL-1beta, regardless of the presence or absence of these alleles. Taken together, these data suggest that the known allelisms in the IL-1beta gene are not major regulators of the in vitro IL-1beta production, but the IL-1RA allele 2 (or an unknown allele strongly associated with it) has a decisive role.
The methylenetetrahydrofolate reductase (MTHFR) C677T mutation has been associated to high homocysteine levels and schizophrenia. Since cytokines are altered in schizophrenia and increments of homocysteine could promote an inflammatory response, it was investigated whether interleukin-6 (IL-6) and tumor necrosis factor alfa (TNFalpha) levels are modulated by the MTHFR genotype. Serum levels of TNFalpha, IL-6, B(12), homocysteine, folate and red blood cell (RBC) folate as well as the MTHFR genotype were determined in a group of schizophrenic patients and compared to those of a control group. RBC folate levels were reduced and homocysteine and the two cytokines' concentrations were elevated in all patients as compared to controls. RBC folate in both heterozygous (CT) and homozygous (TT) patients was significantly different to that of their respective control groups. Homocysteine levels found in patients were significantly higher than those found in controls, only in individuals carrying the TT genotype. Cytokine levels were augmented in the group of patients irrespective of the genotype, and significant differences were found in all cases, except for TNFalpha levels in those subjects carrying the CC genotype. After adjusting for sex, low levels of RBC folate, high levels of homocysteine, both medium and high levels of TNFalpha and high IL-6 levels were associated with schizophrenia. MTHFR genotype was not a risk factor for developing the disease, although a larger sample is required to confirm this finding.
Current antipsychotics have only a limited effect on 2 core aspects of schizophrenia: negative symptoms and cognitive deficits. Minocycline is a second-generation tetracycline that has a beneficial effect in various neurologic disorders. Recent findings in animal models and human case reports suggest its potential for the treatment of schizophrenia. These findings may be linked to the effect of minocycline on the glutamatergic system, through inhibition of nitric oxide synthase and blocking of nitric oxide-induced neurotoxicity. Other proposed mechanisms of action include effects of minocycline on the dopaminergic system and its inhibition of microglial activation.
To examine the efficacy of minocycline as an add-on treatment for alleviating negative and cognitive symptoms in early-phase schizophrenia.
A longitudinal double-blind, randomized, placebo-controlled design was used, and patients were followed for 6 months from August 2003 to March 2007. Seventy early-phase schizophrenia patients (according to DSM-IV) were recruited and 54 were randomly allocated in a 2:1 ratio to minocycline 200 mg/d. All patients had been initiated on treatment with an atypical antipsychotic < or = 14 days prior to study entry (risperidone, olanzapine, quetiapine, or clozapine; 200-600 mg/d chlorpromazine-equivalent doses). Clinical, cognitive, and functional assessments were conducted, with the Scale for the Assessment of Negative Symptoms (SANS) as the primary outcome measure.
Minocycline was well tolerated, with few adverse events. It showed a beneficial effect on negative symptoms and general outcome (evident in SANS, Clinical Global Impressions scale). A similar pattern was found for cognitive functioning, mainly in executive functions (working memory, cognitive shifting, and cognitive planning).
Minocycline treatment was associated with improvement in negative symptoms and executive functioning, both related to frontal-lobe activity. Overall, the findings support the beneficial effect of minocycline add-on therapy in early-phase schizophrenia.
clinicaltrials.gov Identifier: NCT00733057.
Alterations in the inflammatory system have been associated with schizophrenia and major depression, while bipolar disorder has been less studied. Most previous studies examined small samples, and the literature is inconsistent with regard to specific underlying immune mechanisms. In the present study, we examined markers representing different inflammatory pathways, and the aim was to investigate whether the levels of inflammatory parameters in a representative sample of bipolar disorder and schizophrenia are elevated compared to healthy controls, and to investigate whether the inflammatory profile is different between the groups.
Plasma levels of soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6), high-sensitivity CRP (hs-CRP), soluble CD40L ligand (sCD40L), and von Willebrand factor (vWf) were measured with ELISA techniques in a catchment area based sample of consecutively referred patients with severe mental disorders [N = 311, comprising bipolar disorder (n = 125) and schizophrenia (n = 186)] and in healthy volunteers (n = 244).
Plasma levels of sTNF-R1 and vWf were statistically significantly increased in both bipolar disorder and schizophrenia compared to controls (p < 0.00001), and were also increased in unmedicated patients, but there were no major differences between the two diagnostic groups. Controlling for age, gender, ethnicity, cardiovascular disorders, kidney and liver function, and other confounders did not affect the results. There were no differences in other inflammation factors between the groups.
The present results indicate specific alterations of endothelium-related inflammation processes in both bipolar disorder and schizophrenia.
Schizophrenia is still one of the most mysterious and costliest mental disorders in terms of human suffering and societal expenditure. Here, we focus on the key developments in biology, epidemiology, and pharmacology of schizophrenia and provide a syndromal framework in which these aspects can be understood together. Symptoms typically emerge in adolescence and early adulthood. The incidence of the disorder varies greatly across places and migrant groups, as do symptoms, course, and treatment response across individuals. Genetic vulnerability is shared in part with bipolar disorder and recent molecular genetic findings also indicate an overlap with developmental disorders such as autism. The diagnosis of schizophrenia is associated with demonstrable alterations in brain structure and changes in dopamine neurotransmission, the latter being directly related to hallucinations and delusions. Pharmacological treatments, which block the dopamine system, are effective for delusions and hallucinations but less so for disabling cognitive and motivational impairments. Specific vocational and psychological interventions, in combination with antipsychotic medication in a context of community-case management, can improve functional outcome but are not widely available. 100 years after being so named, research is beginning to understand the biological mechanisms underlying the symptoms of schizophrenia and the psychosocial factors that moderate their expression. Although current treatments provide control rather than cure, long-term hospitalisation is not required and prognosis is better than traditionally assumed.
Soluble Interleukin-6 receptor (sIL-6R) levels are strongly related to the levels of Interleukin-6 (IL-6), and sIL-6Rs increase the immune activating properties of IL-6. We estimated sIL-6R serum levels in 25 schizophrenic patients and 25 healthy controls. In the patients, SIL-6R-CSF levels were also measured. The psychopathology was rated according to the AMDP system. We found a significant correlation between serum and cerebrospinal fluid (CSF) levels of sIL-6R, suggesting that serum levels may be a meaningful marker for the central action of sIL-6R. Moreover, significant correlations between the paranoid-hallucinatory syndrome and sIL-6R levels both in serum and CSF were observed. This finding suggests that IL-6 plays a role in the paranoid-hallucinatory symptomatology in schizophrenia. This can be understood regarding the influence of IL-6 to the catecholaminergic neurotransmission. The downregulating effects of neuroleptic treatment to sIL-6R demonstrate that the sIL-6R levels are decreased in the whole group of schizophrenic patients compared to controls.
Autoimmune process is thought to be involved in the pathophysiology in some cases of schizophrenia. Alteration in interleukin (IL) regulation is regarded as additional proof of autoimmunological background in schizophrenia. Most of the research in interleukin activity in schizophrenia has been in Caucasian and some Mongoloid patients. We have studied the serum IL-2 and IL-6 level in psychotropic medication free and antipsychotic medicating schizophrenic patients who are Indian Bengalee by ethnicity.
Twenty psychotropic medication free and 30 antipsychotic medicating schizophrenic patients who fulfilled DSM-IV-TR criteria and 30 of the same age and sex matched controls were recruited. Serum level of IL-2 and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA).
There was a significant decrease of IL-2 and IL-6 in both antipsychotic medicating and psychotropic medication free patients. Further the medicating patients showed lower level of IL-2 and IL-6 than the psychotropic medication free patients.
This is the first study to describe a decrease serum level of IL-6 in schizophrenic patients. The study provides the evidence that some kind of immune dysregulation is involved in pathophysiology of schizophrenia. The study also provides the evidence for the immunosuppressive effect of antipsychotic drugs.
The pathogenesis of schizophrenia and related mental illnesses likely involves multiple interactions between susceptibility genes of small effects and environmental factors. Gene-environment interactions occur across different stages of neurodevelopment to produce heterogeneous clinical and pathological manifestations of the disease. The main obstacle for mechanistic studies of gene-environment interplay has been the paucity of appropriate experimental systems for elucidating the molecular pathways that mediate gene-environment interactions relevant to schizophrenia. Recent advances in psychiatric genetics and a plethora of experimental data from animal studies allow us to suggest a new approach to gene-environment interactions in schizophrenia. We propose that animal models based on identified genetic mutations and measurable environment factors will help advance studies of the molecular mechanisms of gene-environment interplay.
NRG1 is one of the most researched genes associated with schizophrenia. Although three meta-analyses in this area have been published, the results have been inconclusive and even conflicting. Family based studies can be problematical due to the difficulty of synthesizing them with case-control studies. Heterogeneity is another persistently difficult problem which tends to be side-stepped in genetic studies. To deal with these points, we performed a meta-analysis of 26 published case-control and family-based association studies up to September 2008 covering 8049 cases, 8869 controls and 1515 families. The matrix of coancestry coefficient was also calculated using population genetics. Across these studies, the conclusions are as follows: Firstly, only SNP8NRG221132, 420M9-1395(0) and 478B14-848(0) showed significant association in the relatively small sample size. Secondly, we applied both Kazeem's and Lohmueller's methods for synthesizing family and case control studies and there was no statistically significant difference between the results from the two methods, suggesting that either method can be used. In addition, the association analysis of case-control studies was statistically consistent with that of family studies. Finally, the matrix of coancestry coefficient suggested obvious population stratification. The study reveals that one SNP of the NRG1 gene does not contribute significantly to schizophrenia and that population stratification is evident. In future genetic association analysis on complex psychic diseases, haplotype blocks and population structure should be given greater consideration.
Abnormal neuregulin-1 signaling through its receptor (ErbB4) might be associated with schizophrenia, although their neuropathological contribution remains controversial. To assess the role of neuregulin-1 in the dopamine hypothesis of schizophrenia, we used in situ hybridization and immunoblotting to investigate the cellular distribution of ErbB4 mRNA in the substantia nigra of Japanese monkeys (Macaca fuscata) and human postmortem brains. In both monkeys and humans, significant signal for ErbB4 mRNA was detected in substantia nigra dopamine neurons, which were identified by melanin deposits. The expression of ErbB4 mRNA in nigral dopamine neurons was confirmed with an independent RNA probe, as well as with combined tyrosine hydroxylase immunostaining. Immunoblotting appeared to support the observation of in situ hybridization. Immunoreactivity for ErbB4 protein was much more enriched in substantia nigra pars compacta containing dopamine neurons than in neighboring substantia nigra pars reticulata. These observations suggest that ErbB4 is expressed in the dopaminergic neurons of primate substantia nigra and ErbB4 abnormality might contribute to the dopaminergic pathology associated with schizophrenia or other brain diseases.
Although epidermal growth factor (EGF) and neuregulin-1 are neurotrophic factors for mesencephalic dopaminergic neurons and implicated in schizophrenia, the cellular localization and developmental regulation of their receptors (ErbB1-4) remain to be characterized. Here we investigated the distributions of mRNA for ErbB1-4 in the midbrain of the developing mouse with in situ hybridization and immunohistochemistry. The expression of ErbB1 and ErbB2 mRNAs was relatively high at the perinatal stage and frequently colocalized with mRNA for S100beta and Olig2, markers for immature astrocytes or oligodendrocyte precursors. Modest signal for ErbB1 mRNA was also detected in a subset of dopaminergic neurons. ErbB3 mRNA was detectable at postnatal day 10, peaked at postnatal day 18, and colocalized with 2',3'-cyclic nucleotide 3'-phosphodiesterase, a marker for oligodendrocytes. In contrast, ErbB4 mRNA was exclusively localized in neurons throughout development. Almost all of ErbB4 mRNA-expressing cells (94%-96%) were positive for tyrosine hydroxylase in the substantia nigra pars compacta but 66%-78% in the ventral tegmental area and substantia nigra pars lateralis. Conversely, 92%-99% of tyrosine hydroxylase-positive cells expressed ErbB4 mRNA. The robust and restricted expression of ErbB4 mRNA in the midbrain dopaminergic neurons suggests that ErbB4 ligands, neuregulin-1 and other EGF-related molecules, contribute to development or maintenance of this neuronal population.
Both schizophrenia and oxidative stress have been associated with immune system abnormalities in interleukin-2 and -6 (IL-2; IL-6) and increases in superoxide dismutase (SOD) activity. These abnormalities may improve during antipsychotic drug treatment that reduces symptoms in schizophrenic patients.
Subjects included 30 healthy controls (HC) and 78 schizophrenic (SCH) in-patients who were randomly assigned to 12 weeks of double-blind treatment with risperidone 6 mg/day or haloperidol 20 mg/day. Ratings using the Positive and Negative Syndrome Scale (PANSS) were correlated with blood SOD and serum IL-2 levels.
SCH patients who were medication-free for 2 weeks had greater SOD, IL-2, and IL-6 levels than HC. At baseline, these SOD elevations were associated with higher PANSS total scores and the IL-2 elevations with lower PANSS positive symptom scores. The SOD and IL-2 levels in the SCH were also positively correlated. After treatment, PANSS positive symptoms and both SOD and IL-2 showed a significant decrease, but IL-6 showed no change. The SOD and IL-2 reductions were correlated with the reductions in PANSS total score, and SOD reductions also correlated with positive subscore reductions. Females showed these associations more strongly than males.
Our results suggest that the dysregulation in the cytokine system and oxidative stress in patients with schizophrenia is implicated in clinical symptoms and is improved at least partially with antipsychotic treatment. The stronger associations in females deserve further study and confirmation.
There is increasing evidence of immune involvement in both schizophrenia and autism. Of particular interest are striking abnormalities in the expression of immune-related molecules such as cytokines in the brain and cerebral spinal fluid (CSF). It is proposed that this represents a permanent state of brain immune dysregulation, which begins during early development. One possibility is that maternal infection, a known risk factor for schizophrenia and autism, sets this immune activation in motion. Several animal models are being used to investigate this hypothesis. There is also recent evidence that, among schizophrenic subjects, those associated with maternal infection display a distinctive pathology, which suggests that diverse causes for this disorder may explain some of its heterogeneity. The human and animal results related to immune involvement suggest novel therapeutic avenues based on immune interventions.
Ligands for the epidermal growth factor receptor ErbB1, such as epidermal growth factor (EGF) and transforming growth factor alpha (TGFalpha), negatively regulate synaptic maturation of GABAergic neurons in the developing neocortex. Here, we evaluated the effects of these ligands in vivo on developing inhibitory neurons in the dentate gyrus. Hippocampal slices were prepared from postnatal mice repeatedly challenged with EGF or from transgenic mice overexpressing TGFalpha. We monitored paired pulse depression of field population spikes evoked by perforant path stimulation to estimate the strength of local inhibition. Administration of EGF increased the paired pulse ratio, suggesting a reduction of inhibitory strength. A similar reduction was observed in TGFalpha transgenic mice. Monitoring miniature and evoked synaptic currents, we estimated EGF effects on synaptic input and output of GABAergic neurons. EGF treatment diminished the amplitude of excitatory postsynaptic currents (EPSCs) in the GABAergic neurons without affecting their miniature EPSCs. EGF also affected output strength of the GABAergic neurons: The frequency of miniature inhibitory postsynaptic currents (IPSCs) and the evoked IPSC/evoked EPSC ratio were decreased in granule cells. In parallel, EGF down-regulated the protein level of vesicular GABA transporter. Thus, ErbB1 ligands influence GABAergic inhibitory synaptic transmission in the developing dentate gyrus.
Many reports suggest that schizophrenia is associated with the inflammatory response mediated by cytokines, and nuclear factor-kappa B (NF-kappaB) regulates the expression of cytokines. However, it remains unclear whether the interaction between NF-kappaB and cytokines is implicated in schizophrenia and whether the effect of neuroleptics treatment for 4 weeks is associated with the alteration of cytokines.
Sixty-five healthy subjects and 83 first-episode schizophrenic patients who met DSM-IV criteria and who were never treated with neuroleptics previously were included. Serum levels of cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) were examined by using sandwich enzyme immunoassay (EIA). Peripheral blood mononuclear cell (PBMC) mRNA expressions of cytokines (IL-1beta, TNF-alpha) and NF-kappaB were detected by using semiquantitative reverse transcription polymerase chain reaction (RT-PCR). NF-kappaB activation was examined by using transcription factor assay kits.
Schizophrenic patients showed significantly higher serum levels and PBMC mRNA expressions of IL-1beta and TNF-alpha compared with healthy subjects. However, treatment with the neuroleptic risperidone for 4 weeks significantly decreased serum levels and PBMC mRNA expressions of IL-1beta in schizophrenic patients. NF-kappaB activation and PBMC mRNA expression in patients were significantly higher than those in healthy subjects. Furthermore, PBMC mRNA expressions of IL-1beta and TNF-alpha were positively correlated to NF-kappaB activation in both schizophrenic patients and healthy control subjects.
Schizophrenic patients showed activation of the cytokine system and immune disturbance. NF-kappaB activation may play a pivotal role in schizophrenia through interaction with cytokines.
Epidermal growth factor (EGF) has a neurotrophic activity on developing midbrain dopaminergic neurons. We investigated developmental effects of peripheral EGF administration on dopaminergic neurons in midbrain slice preparations containing ventral tegmental area (VTA). Subcutaneous EGF administration to mouse neonates triggered phosphorylation of EGF receptors (ErbB1 and ErbB2) in the midbrain region, suggesting its penetration through the blood-brain barrier. We repeated EGF administration in postnatal mice and examined synaptic transmission in the VTA with electrophysiological recordings. Subchronic EGF treatment increased the amplitude of field excitatory postsynaptic potentials evoked by stimulation of the anterior VTA. To analyze the EGF effect at a single cell level, dopaminergic neurons were identified by their characteristic hyperpolarizing activated currents in whole cell recording. In these dopaminergic neurons, EGF effects the amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs) without affecting their frequency. In agreement, EGF also enhanced the AMPA/NMDA ratio of evoked EPSCs in the dopaminergic neurons. In contrast, EGF effects on mEPSCs of neighboring neurons not exhibiting hyperpolarizing activated currents were modest or insignificant. Thus, these results suggest that circulating EGF substantially influences the physiological properties of developing midbrain dopaminergic neurons in perinatal and postnatal mice.