Article

Population-based and family based association study of 5′UTR polymorphism of the Reelin gene and schizophrenia

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Abstract

Reelin is a glycoprotein involved in the migration and positioning of proliferating neurons and synaptic connectivity during neurodevelopment. It may also modulate neuronal plasticity throughout life. Therefore, the reelin gene is a candidate gene for schizophrenia. We examined the association of the CGG repeat polymorphism in the 5'-untranslated region of the reelin gene with schizophrenia in 266 unrelated French Caucasian patients, 156 of their parents, and 103 controls. We found no difference in the allele distribution between patients and controls although there was a significant higher prevalence of the genotype 8-8 in controls (CLUMP T3: chi(2) = 6.3, P = 0.035). There was no significant transmission disequilibrium in intrafamilial analysis. To refine our phenotypic characterization and in accordance with converging evidence suggesting that treatment resistance is associated with indices of abnormal neurodevelopment, we studied the association between reelin gene polymorphism and response to antipsychotics. Patients who responded to antipsychotics had a higher frequency of both the (CGG)(10) allele and (CGG)(10)-containing genotypes (P = 0.02; P = 0.006, respectively), with an odd ratio for genotypes of 4.2 (CI = [1.4;12.4]). Our results weakly support an association of reelin gene variants with schizophrenia as a whole, yet suggest that reelin could be associated with treatment-resistant schizophrenia.

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... In a study of 193 French patients (45 resistant, 148 responsive) considering the 5'UTR (ccG repeat) polymorphism of the reelin gene, a significantly higher frequency of ccG10 alleles in treatment-resistant patients was found [34]. ...
... All treatment-resistant patients were prescribed clozapine, while all treatmentresponsive patients were prescribed haloperidol. Unfortunately, none of these findings are reported to survive multiple-testing correction: four do not report correction [31,33,34,36] and two report their findings becoming non-significant after correction [32,37]. ...
... Reelin Studies identified also suggest that treatmentresistance may be differentiated from treatment-responsive schizophrenia by greater repetition of the CCG repeat for the 5'UTR polymorphism on the reelin gene [34]. However, this was also not corrected for multiple-testing and this polymorphism had previously been found to lack an association with schizophrenia [65], despite reelin abnormalities having long been associated with schizophrenia [66]; unfortunately no other studies appear to look at an association with treatment response. ...
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Background: Schizophrenia is a highly heterogeneous disorder, and around a third of patients are treatment-resistant. The only evidence-based treatment for these patients is clozapine, an atypical antipsychotic with relatively weak dopamine antagonism. It is plausible that varying degrees of response to antipsychotics reflect categorically distinct illness subtypes, which would have significant implications for research and clinical practice. If these subtypes could be distinguished at illness onset, this could represent a first step towards personalised medicine in psychiatry. This systematic review investigates whether current evidence supports conceptualising treatment-resistant and treatment-responsive schizophrenoa as categorically distinct subtypes. Method: A systematic literature search was conducted, using PubMed, EMBASE, PsycInfo, CINAHL and OpenGrey databases, to identify all studies which compared treatment-resistant schizophrenia (defined as either a lack of response to two antipsychotic trials or clozapine prescription) to treatment-responsive schizophrenia (defined as known response to non-clozapine antipsychotics). Results: Nineteen studies of moderate quality met inclusion criteria. The most robust findings indicate that treatment-resistant patients show glutamatergic abnormalities, a lack of dopaminergic abnormalities, and significant decreases in grey matter compared to treatment-responsive patients. Treatment-resistant patients were also reported to have higher familial loading; however, no individual gene-association study reported their findings surviving correction for multiple comparisons. Conclusions: Tentative evidence supports conceptualising treatment-resistant schizophrenia as a categorically different illness subtype to treatment-responsive schizophrenia. However, research is limited and confirmation will require replication and rigorously controlled studies with large sample sizes and prospective study designs.
... RELN methylation may, however, increase with age as well (Tamura et al. 2007). RELN expression is also reduced by its promoter-region trinucleotide repeat lengthening (Persico et al. 2006) which in turn is associated with treatment-resistant schizophrenia (Goldberger et al. 2005). In addition to its promoter-region, however, only a few direct genetic associations between schizophrenia and RELN exist (Kahler et al. 2008, Shifman et al. 2008, thus leaving the specific mechanisms underlying the disorder liability somewhat unclear. ...
... In our Finnish sample, however, none of the alleles exceeded the length of 15 repeats (III). This is noteworthy, since the longer alleles are associated with autism (Persico et al. 2001) and treatment-resistant schizophrenia (Goldberger et al. 2005), possibly via decreased RELN expression (Persico et al. 2006). ...
... On the other hand, one of the factors increasing the RELN methylation may be aging (Tamura et al. 2007). That the trinucleotide repeat lengthening in the RELN promoter-region, affecting its expression levels (Persico et al. 2006), appears in treatment-resistant schizophrenia (Goldberger et al. 2005) provides further evidence for RELN actions in the background of schizophrenia. Interestingly, a long allele of this RELN promoter-region STR showed association in our study with the earlier age of schizophrenia onset. ...
Article
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Schizophrenia, affecting about 1% of population worldwide, is a severe mental disorder characterized by positive and negative symptoms, such as psychosis and anhedonia, as well as cognitive deficits. At present, schizophrenia is considered a complex disorder of neurodevelopmental origin with both genetic and environmental factors contributing to its onset. Although a number of candidate genes for schizophrenia have been highlighted, only very few schizophrenia patients are likely to share identical genetic liability. This study is based on the nation-wide schizophrenia family sample of the National Institute for Health and Welfare, and represents one of the largest and most well-characterized familial series in the world. In the first part of this study, we investigated the roles of the DTNBP1, NRG1, and AKT1 genes in the background of schizophrenia in Finland. Although these genes are associated with schizophrenia liability in several populations, any significant association with clinical diagnostic information of schizophrenia remained absent in our sample of 441 schizophrenia families. In the second part of this study, we first replicated schizophrenia linkage on the long arm of chromosome 7 in 352 schizophrenia families. In the following association analysis, we utilized additional clinical disorder features and intermediate phenotypes – endophenotypes - in addition to diagnostic information from altogether 290 neuropsychologically assessed schizophrenia families. An intragenic short tandem repeat allele of the regional RELN gene, supposed to play a role in the background of several neurodevelopmental disorders, showed significant association with poorer cognitive functioning and more severe schizophrenia symptoms. Additionally, this risk allele was significantly more prevalent among the individuals affected with schizophrenia spectrum disorders. We have previously identified linkage of schizophrenia and its cognitive endophenotypes on the long arms of chromosomes 2, 4, and 5. In the last part of this study, we selected altogether 104 functionally relevant candidate genes from the linked regions. We detected several promising associations, of which especially interesting are the ERBB4 gene, showing association with the severity of schizophrenia symptoms and impairments in traits related to verbal abilities, and the GRIA1 gene, showing association with the severity of schizophrenia symptoms. Our results extend the previous evidence that the genetic risk for schizophrenia is at least partially mediated via the effects of the candidate genes and their combinations on relevant brain systems, resulting in alterations in different disorder domains, such as the cognitive deficits. Skitsofrenia, johon sairastuu elinaikanaan jopa 1,0 % maailman väestöstä, on vakava mielenterveyden häiriö. Sen keskeisiä piirteitä ovat positiiviset ja negatiiviset oireet, kuten aistiharhat ja tunteiden latistuminen, sekä heikentynyt kognitiivinen suoriutuminen. Nykykäsityksen mukaan skitsofrenia on keskushermoston kehityshäiriöstä johtuva monitekijäinen sairaus, jonka puhkeamiseen vaikuttavat sekä perimä että ympäristötekijät. Vaikka lukuisia skitsofrenialle altistavia geenimuotoja on tunnistettu, todennäköisesti vain harvoilla sairastuneilla on taudin taustalla samanlainen altistavien geenimuotojen yhdistelmä. Tämä tutkimus perustuu Terveyden ja hyvinvoinnin laitoksen keräämään suomalaiseen skitsofreniaperheaineistoon, joka on laajuudeltaan merkittävä koko maailmankin mittakaavassa. Tutkimuksen ensimmäisessä osatyössä kartoitettiin geenien DTNBP1, NRG1 ja AKT1 merkitystä skitsofrenian taustalla. Vaikka näiden geenien eri muodot on yhdistetty lisääntyneeseen skitsofreniariskiin useissa eri väestöryhmissä, tutkimuksessamme ei havattu merkittävää yhteyttä sairauden ja kyseisten geenien välillä 441 perheen aineistossamme. Tutkimuksen toisessa ja kolmannessa osatyössä toistimme aluksi 352 perheen aineistossa skitsofreniakytkennän kromosomin 7 pitkän käsivarren alueelle. Seuraavassa vaiheessa hyödynsimme sairausdiagnoositiedon lisäksi erilaisiin kliinisiin sairauspiirteisiin ja välimuotoisiin ilmiasupiirteisiin – endofenotyyppeihin - perustuvia muuttujia yhteensä 290 neuropsykologisesti testatun perheen aineistossa. Havaitsimme kytkeytyvällä kromosomialueella sijaitsevassa RELN-geenissä sijaitsevan geenimerkin yhdistyvän sekä heikentyneeseen kognitiiviseen suoriutumiseen että vaikeampiin skitsofreniaoireisiin. Mielenkiintoisesti RELN-geenin eri muodot näyttäisivät vaikuttavan useiden keskushermoston kehityksellisten sairauksien taustalla. Tutkimusryhmämme on aiemmin havainnut sekä skitsofrenian että sen kognitiivisten endofenotyyppien kytkeytymisen kromosomien 2, 4 ja 5 pitkien käsivarsien alueelle. Viimeisessä osatyössä valitsimme näiltä alueilta yhteensä 104 geeniä, ja havaitsimme lukuisia lupaavia yhteyksiä, joista erityisen kiinnostavia olivat geenit ERBB4, joka yhdistyi vaikeampiin skitsofreniaoireisiin ja heikentyneeseen kielelliseen suoriutumiseen, sekä GRIA1, joka yhdistyi vaikeampiin skitsofreniaoireisiin. Tutkimuksemme perusteella skitsofrenian geneettinen tausta voi ainakin osin selittyä yksittäisten geenien vaikutuksella keskushermoston kehitykseen ja toimintoihin, mikä voi ilmetä erityisesti vaihteluna sairauteen liittyvissä piirteissä, kuten kognitiivisissa toiminnoissa.
... A number of negative gene association studies between RELN and schizophrenia have been published as well (Akahane et al. 2002;Chang et al. 2011;Goldberger et al. 2005;Huang and Chen, 2006). Because of its association with increased risk of autism, the 5′ untranslated region of the RELN gene has been investigated for conferring risk for the development of schizophrenia. ...
... Because of its association with increased risk of autism, the 5′ untranslated region of the RELN gene has been investigated for conferring risk for the development of schizophrenia. However, this region has not been found to be associated with schizophrenia (Akahane et al. 2002;Goldberger et al. 2005;Huang and Chen, 2006). SNPs in RELN's promoter region have shown no association with schizophrenia in a Han Chinese population sample (Chang et al. 2011). ...
Article
Reelin is a glycoprotein that serves important roles both during development (regulation of neuronal migration and brain lamination) and in adults (maintenance of synaptic function). A number of neuropsychiatric disorders including autism, schizophrenia, bipolar disorder, major depression, Alzheimer's disease and lissencephaly share a common feature of abnormal Reelin expression in the brain. Altered Reelin expression has been hypothesized to impair neuronal connectivity and synaptic plasticity, leading ultimately to the cognitive deficits present in these disorders. The mechanisms for abnormal Reelin expression in some of these disorders are currently unknown although possible explanations include early developmental insults, mutations, hypermethylation of the promoter for the Reelin gene (RELN), miRNA silencing of Reelin mRNA, and Reelin processing abnormalities. Increasing Reelin expression through pharmacological therapies may help ameliorate symptoms resulting from Reelin deficits. This article is part of a Special Issue entitled 'Neurodevelopment Disorder'.
... Therefore, the association of this RELN variant (rs7341475) with schizophrenia remained inconclusive . Additionally, the association of RELN with schizophrenia was also supported by early genomewide analysis using microsatellite markers and studies of working memory in schizophrenia patients as well as population and family based association analyses (Ekelund et al. 2000; Goldberger et al. 2005; Kahler et al. 2008; Wedenoja et al. 2008; Wedenoja et al. 2010). However, most of the studies were conducted in populations of European ancestry, and studies in other ethnic populations were rather limited. ...
... In summary, we present evidence that the genetic variants in RELN are associated with schizophrenia in Han Chinese population. Considering the results of previous studies in Ashkenazi Jews and European populations (Goldberger et al. 2005; Kahler et al. 2008; Shifman et al. 2008; Wedenoja et al. 2008 Wedenoja et al. , 2010), RELN is likely a common risk gene for schizophrenia in major populations worldwide. The haplotype analysis of these SNPs further supported the association (global P 1.0 10 – 5 ). ...
Article
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Unlabelled: Abstract Objectives. Several lines of evidence have shown that both RELN mRNA and protein are possibly down-regulated in the brain of schizophrenia patients. Recent association studies in European populations suggested RELN as a risk gene for schizophrenia. In this study, we test if RELN contributes to the risk of schizophrenia in Chinese population. Methods. We conducted case-control association analysis of 19 representative single nucleotide polymorphisms (SNPs) spanning the entire region of RELN in two independent Han Chinese samples from southwestern China (the Kunming sample and the Yuxi sample). Results. We identified six SNPs significantly associated with schizophrenia in the Kunming sample and four of them remained significant in the combined samples (the P values range from 0.006 to 4.0 × 10(-5)). Haplotype analysis also suggested significant associations for the haplotypes incorporating the six significant SNPs (global P < 1.0 × 10(-5)). Additionally, we also observed several other haplotypes (defined by a different set of SNPs) significantly associated with schizophrenia in the Kunming sample. However, the reported association of rs7341475 in Ashkenazi Jews was not significant in Han Chinese. Conclusions: Our findings demonstrate that RELN is a susceptibility gene for schizophrenia in Chinese population, and it is likely a common risk gene for schizophrenia in major populations worldwide.
... Previous studies showed that RELN mRNA and protein levels are reduced by approximately 50% in various cortical structures of postmortem brain from patients diagnosed with schizophrenia or bipolar illness with psychosis (Fatemi et al., 2001; Eastwood and Harrison, 2003), as well as in the serum of schizophrenic patients (Fatemi, 2001), which is in line with the findings of an increased methylation of the promoter region of the gene in SZ (Grayson et al., 2005). However, studies related to the RELN gene polymorphism and SZ are not abundant (Akahane et al., 2002; Goldberger et al., 2005) and do not cover the entire variation panel of the gene nor its haplotype blocks. In a population and familial association study of a RELN polymorphism (a CGG repeat in the 5′ UTR of the gene) and SZ, Goldberger et al. (2005) found that patients who responded to antipsychotics had a higher frequency of both the (CGG)(10) allele and (CGG)(10)- containing genotypes ( P = 0.02 and P = 0.006, respectively), clearly demonstrating the key importance of endophenotype-based approaches to reveal unseen genetic associations. ...
... However, studies related to the RELN gene polymorphism and SZ are not abundant (Akahane et al., 2002; Goldberger et al., 2005) and do not cover the entire variation panel of the gene nor its haplotype blocks. In a population and familial association study of a RELN polymorphism (a CGG repeat in the 5′ UTR of the gene) and SZ, Goldberger et al. (2005) found that patients who responded to antipsychotics had a higher frequency of both the (CGG)(10) allele and (CGG)(10)- containing genotypes ( P = 0.02 and P = 0.006, respectively), clearly demonstrating the key importance of endophenotype-based approaches to reveal unseen genetic associations. In complex diseases, as pointed out by Gottesman et al. (2003), genotypes are " probabilistic prognosticators of disease " . ...
Article
An abnormality in neurodevelopment is one of the most robust etiologic hypotheses in schizophrenia (SZ). There is also strong evidence that genetic factors may influence abnormal neurodevelopment in the disease. The present study evaluated in SZ patients, whose brain structural data had been obtained with magnetic resonance imaging (MRI), the possible association between structural brain measures, and 32 DNA polymorphisms, located in 30 genes related to neurogenesis and brain development. DNA was extracted from peripheral blood cells of 25 patients with schizophrenia, genotyping was performed using diverse procedures, and putative associations were evaluated by standard statistical methods (using the software Statistical Package for Social Sciences - SPSS) with a modified Bonferroni adjustment. For reelin (RELN), a protease that guides neurons in the developing brain and underlies neurotransmission and synaptic plasticity in adults, an association was found for a non-synonymous polymorphism (Val997Leu) with left and right ventricular enlargement. A putative association was also found between protocadherin 12 (PCDH12), a cell adhesion molecule involved in axonal guidance and synaptic specificity, and cortical folding (asymmetry coefficient of gyrification index). Although our results are preliminary, due to the small number of individuals analyzed, such an approach could reveal new candidate genes implicated in anomalous neurodevelopment in schizophrenia.
... Downregulation in SZ Patients _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The reduction of prefrontal cortical reelin expression that occurs in GABAergic neurons, together with the downregulation of GAD 67 expression , are among the most consistent neuropathological findings in postmortem studies of SZ cortex (Knable et al., 2004). Several lines of evidence support the hypothesis that the expression deficit of reelin and GAD 67 detected in SZ brains cannot be explained by a RELN or GAD 67 gene haploinsufficiency (Costa et al., 2003; Goldberger et al., 2005). Converging evidence suggests that in SZ patients, the reduced reelin expression found in cortical GABAergic interneurons is related to the hypermethylation of its promoter (Abdolmaleky et al., 2005; Grayson et al., 2005). ...
... of SZ Patients _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Thus far, the evidence we have collected strongly supports the view that SZ neuropathology includes a specific molecular dysfunction of cortical GABAergic neurons (Goldberger et al., 2005; Guidotti et al., 2000). We have found that this specific neuronal dysfunction is characterized by a selective DNMT1 overexpression in GABAergic cortical neurons of layers I, II, and III, which may be the cause of the hypermethylation of reelin, GAD 67 , NMR2A receptor, a7 nicotinic receptor, and possibly other gene promoters, causing a subsequent reduction in the expression of the corresponding mRNAs (Costa et al., 2001; Grayson et al., 2005 Grayson et al., , 2006 Guidotti et al., 2000 Guidotti et al., , 2005 Martin et al., 2004). ...
Article
This chapter describes the epigenetic targets in γ‐aminobutyric acid (GABAergic) neurons to treat schizophrenia (SZ). In the cortical GABAergic neurons of SZ patients, transcriptional downregulation of genes, encoding several proteins critical for neuronal plasticity, such as reelin and GAD67, is related to an epigenetic hypermethylation of their corresponding promoters by DNA methyltransferase 1 (DNMT1), which is selectively overexpressed in these neurons. Epigenetic changes in the regulation of reelin and GAD67 contribute to the sculpting of specific neuroanatomical, neurochemical, and behavioral endophenotypes in SZ. These changes can be treated by targeting the aberrations in epigenetic function detected in the cortical GABAergic neurons of SZ patients. A multicenter double‐blind study shows that atypical antipsychotics have a faster onset of response when combined with valproic acid (VPA). VPA is a histone deacetylase (HDAC) inhibitor that suggests that supplementation of atypical anti-psychotics with HDAC inhibitors elicits a faster onset of specific epigenetic transcriptional changes underlying antipsychotic efficacy. The findings discussed in the chapter offer new opportunities for “epigenetic treatments” aimed at decreasing the hypermethylation of promoters that are associated with GABAergic dysfunction in SZ.
... Altered reelin expression may result in the impairment of neuronal connectivity and synaptic plasticity, leading to the cognitive deficits observed in schizophrenia [79]. The study by Goldberger and colleagues [51] provides further support for the involvement of reelin in schizophrenia, with (CGG) 10 alleles and genotypes in particular being associated with TRS. Another gene involved in synaptic functioning, SNAP25 synaptosome-associated protein 25 (SNAP-25), was found to be related to TRS. ...
Article
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Treatment-resistant schizophrenia (TRS) is often associated with severe burden of disease, poor quality of life and functional impairment. Clozapine is the gold standard for the treatment of TRS, although it is also known to cause significant side effects in some patients. In view of the burgeoning interest in the role of genetic factors in precision psychiatry, we conducted a scoping review to narratively summarize the current genetic factors associated with TRS, clozapine resistance and side effects to clozapine treatment. We searched PubMed from inception to December 2022 and included 104 relevant studies in this review. Extant evidence comprised associations between TRS and clozapine resistance with genetic factors related to mainly dopaminergic and serotoninergic neurotransmitter systems, specifically, TRS and rs4680, rs4818 within COMT, and rs1799978 within DRD2; clozapine resistance and DRD3 polymorphisms, CYP1A2 polymorphisms; weight gain with LEP and SNAP-25 genes; and agranulocytosis risk with HLA-related polymorphisms. Future studies, including replication in larger multi-site samples, are still needed to elucidate putative risk genes and the interactions between different genes and their correlations with relevant clinical factors such as psychopathology, psychosocial functioning, cognition and progressive changes with treatment over time in TRS and clozapine resistance.
... A number of studies have suggested some form of a relationship between hypoactivity of Reelin and neuropsychiatric disorders 3,10 . For example, genomic studies reproducibly indicated that variations of the Reelin gene are associated with schizophrenia [26][27][28][29] , bipolar disorder 29,30 , and ASD 31,32 . Single nucleotide polymorphisms in the Reelin receptor ApoER2, as well as decreases in its mRNA, are also significant risk factors for schizophrenia and Scientific RepoRts | 6:28636 | DOI: 10.1038/srep28636 bipolar disorder 33,34 . ...
Article
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The secreted glycoprotein Reelin is believed to play critical roles in the pathogenesis of several neuropsychiatric disorders. The highly basic C-terminal region (CTR) of Reelin is necessary for efficient activation of its downstream signaling, and the brain structure of knock-in mice that lack the CTR (ΔC-KI mice) is impaired. Here, we performed a comprehensive behavioral test battery on ΔC-KI mice, in order to evaluate the effects of partial loss-of-function of Reelin on brain functions. The ΔC-KI mice were hyperactive and exhibited reduced anxiety-like and social behaviors. The working memory in ΔC-KI mice was impaired in a T-maze test. There was little difference in spatial reference memory, depression-like behavior, prepulse inhibition, or fear memory between ΔC-KI and wild-type mice. These results suggest that CTR-dependent Reelin functions are required for some specific normal brain functions and that ΔC-KI mice recapitulate some aspects of neuropsychiatric disorders, such as schizophrenia, bipolar disorder, and autism spectrum disorder.
... Following the initial observation that REELIN mRNA levels are reduced in patients with schizophrenia (Impagnatiello et al., 1998), several investigators reported a deficiency in Reelin expression in different groups of psychiatric subjects, including those with bipolar disorder (Knuesel, 2010). The reduction in Reelin expression occurs most likely through epigenetic mechanisms that affect promoter methylation (Veldic et al., 2004;Grayson et al., 2006) although evidence for genetic association between schizophrenia and REELIN polymorphisms also exists in patient subpopulations (Goldberger et al., 2005;Wedenoja et al., 2008). Furthermore, Reelin has been reported to suppress schizophreniform symptoms in mice (Ishii et al., 2015). ...
Article
Full-text available
Reelin is a neuronal glycoprotein secreted by the Cajal-Retzius cells in marginal regions of the cerebral cortex and the hippocampus where it plays important roles in the control of neuronal migration and the formation of cellular layers during brain development. This 3461 residue-long protein is composed of a signal peptide, an F-spondin-like domain, eight Reelin repeats (RR1-8), and a positively charged sequence at the C-terminus. Biochemical data indicate that the central region of Reelin binds to the low-density lipoprotein receptors ApoER2 and VLDLR, leading to the phosphorylation of the intracellular adaptor protein Dab1. After secretion, Reelin is rapidly degraded in three major fragments, but the functional significance of this degradation is poorly understood. Probably due to its large mass and the complexity of its architecture, the high-resolution, three-dimensional structure of Reelin has never been determined. However, the crystal structures of some of the reelin repeats have been solved, providing important insights into their fold and the interaction with the ApoER2 receptor. This review discusses the current findings on the structure of Reelin and its binding to the ApoER2 and VLDLR receptors, and we discuss some areas where proteomics and structural biology can help understanding Reelin function in brain development and human health.
... Ce facteur neurotrophique a son expression modulée par plusieurs mécanismes dont la méthylation de son promoteur (Tsankova et al, 2006).Harrison et Weinberger, 2005). Une association a été montrée dans l'autisme et, d'après les résultats de notre laboratoire, avec la réponse au traitement dans la schizophrénie (Goldberger et al, 2005). La variation du taux de reeline dans la schizophrénie semble être liée à une hyperméthylation de son promoteur (Noh et al, 2005). ...
... As over-expression of Reelin in a transgenic mouse model led to reversal of various behavioural abnormalities (Teixeira et al., 2011), this molecule has been suggested as a marker for stress resilience. Genetic alterations of the RELN gene have been shown in autistic (Persico et al., 2001) and schizophrenic patients (Goldberger et al., 2005) but no study has investigated the association of RELN gene polymorphisms with MDD or resilience to date, leaving it as a good candidate for further research investigations. ...
... Successes have been reported for common variants, in which the same variants were detected by both designs [9,10] . However, inconsistency was also observed [11,12]. It is not clear how family-and population-based analyses behave on rare variants. ...
Article
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Both family- and population-based samples are used to identify genetic variants associated with phenotypes. Each strategy has demonstrated advantages, but their ability to identify rare variants and genes containing rare variants is unclear. To compare these two study designs in the identification of rare causal variants, we applied various methods to the population- and family-based data simulated by the Genetic Analysis Workshop 17 with knowledge of the simulated model. Our results suggest that different variants can be identified by different study designs. Family-based and population-based study designs can be complementary in the identification of rare causal variants and should be considered in future studies.
... Recent studies support the hypothesis that either a genetic (19). The complex pattern of reelin expression is consistent with evidence that this protein has multiple roles in brain development and adult brain function (20). In the adult mammalian brain, reelin has been proposed to influence synaptogenesis and neural plasticity and to favor memory formation (8)(9)(10). ...
Article
Reelin is an extracellular signaling glycoprotein, which plays a significant role in cytoarchitectonic pattern formation of different brain areas during development. Reelin gene is located on chromosome 7q22. The aim of this study is to investigate the possible association of the following reelin polymorphisms SNP Intron12A/C (rs727531), SNP Exon15A/G (rs2072403), SNP Intron15G/T (rs2072402), SNP Exon22c/g (rs362691), SNP Intron41G/T (rs362719) and SNP Intron59C/T (rs736707) in the pathogenesis of Alzheimer 's disease and the frequency of these polymorphisms in the population of Northern Greece. The study included two groups, A and B. Group A consisted of 50 patients with Alzheimer 's disease and group B of 70 healthy controls. Genomic DNA isolated from blood was used for PCR and subsequent RFLP analysis. According to our results, the exon 22 C/G marker of Reelin is significantly associated with Alzheimer 's disease in the Greek population but the Likelihood Ratio Test shows that the GT haplotype ++ this polymorphism does not affect the phenotype of group A in relation to Group B. This is the first report on a Greek population-based approach.
... RELN's relationship with schizophrenia is well-supported by linkage or association studies, 45,46 and it has also been shown to be associated with treatment resistance. 57 RELN expression is markedly reduced (by 50%) in mRNA and protein in post mortem brain tissue from schizophrenia patients. 58 Epigenetic abnormalities have also been found; hypermethylation in the promotor region may be an explanation for the reduced expression of RELN in the brain. ...
Article
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Although schizophrenia is generally considered to occur as a consequence of multiple genes that interact with one another, very few methods have been developed to model epistasis. Phenotype definition has also been a major challenge for research on the genetics of schizophrenia. In this report, we use novel statistical techniques to address the high dimensionality of genomic data, and we apply a refinement in phenotype definition by basing it on the occurrence of brain changes during the early course of the illness, as measured by repeated magnetic resonance scans (i.e., an 'intermediate phenotype.') The method combines a machine-learning algorithm, the ensemble method using stochastic gradient boosting, with traditional general linear model statistics. We began with 14 genes that are relevant to schizophrenia, based on association studies or their role in neurodevelopment, and then used statistical techniques to reduce them to five genes and 17 single nucleotide polymorphisms (SNPs) that had a significant statistical interaction: five for PDE4B, four for RELN, four for ERBB4, three for DISC1 and one for NRG1. Five of the SNPs involved in these interactions replicate previous research in that, these five SNPs have previously been identified as schizophrenia vulnerability markers or implicate cognitive processes relevant to schizophrenia. This ability to replicate previous work suggests that our method has potential for detecting a meaningful epistatic relationship among the genes that influence brain abnormalities in schizophrenia.
... Reelin is an extracellular matrix protein thought to control cell-cell interactions critical for cell positioning and neuronal migration during brain development. In one genetic study, 51 it was suggested that reelin is associated with treatment-resistant schizophrenia, and it has been shown that levels of reelin and its mRNA are significantly reduced in several brain areas of patients with undifferentiated or paranoid schizophrenia. 52 Our results provide the first evidence of a possible link between NPAS3 and the efficacy of an antipsychotic treatment. ...
Article
A whole genome association study was performed in a phase 3 clinical trial conducted to evaluate a novel antipsychotic, iloperidone, administered to treat patients with schizophrenia. Genotypes of 407 patients were analyzed for 334,563 single nucleotide polymorphisms (SNPs). SNPs associated with iloperidone efficacy were identified within the neuronal PAS domain protein 3 gene (NPAS3), close to a translocation breakpoint site previously observed in a family with schizophrenia. Five other loci were identified that include the XK, Kell blood group complex subunit-related family, member 4 gene (XKR4), the tenascin-R gene (TNR), the glutamate receptor, inotropic, AMPA 4 gene (GRIA4), the glial cell line-derived neurotrophic factor receptor-alpha2 gene (GFRA2), and the NUDT9P1 pseudogene located in the chromosomal region of the serotonin receptor 7 gene (HTR7). The study of these polymorphisms and genes may lead to a better understanding of the etiology of schizophrenia and of its treatment. These results provide new insight into response to iloperidone, developed with the ultimate goal of directing therapy to patients with the highest benefit-to-risk ratio.
... Exclusion criteria were psychotic symptoms primarily caused by alcohol, drug abuse, or other clinical diagnosis, including major cytogenetic abnormalities and mental retardation. The final panel of samples (n ϭ 188: 134 male samples, 54 female samples) included sporadic SCZ subjects from five different centers, including 16 cases of childhood-onset SCZ from National Institute of Mental Health, United States (2); 24 cases of adult-onset SCZ from Paris, France (18); 71 cases of adult-onset SCZ from Montreal, Canada (19); 45 cases of adult-onset SCZ from New York, United States (20); and 32 cases of adult-onset SCZ from Tunis, Tunisia. Detailed descriptions of ascertainment strategy, diagnostic tools, and criteria were reported by each center in previous publications (see above). ...
Article
Schizophrenia (SCZ) is one of the most disabling psychiatric disorders. It is thought to be due to a complex interplay between polygenic and various environmental risk factors, although recent reports on genomic copy number variations suggest that a fraction of the cases could result from variably penetrant de novo variants. The gene encoding the synaptic motor protein kinesin 17 (KIF17) involved in glutamatergic synapse is a candidate gene for SCZ. As part of our Synapse to Disease project, we resequenced KIF17 in a cohort of individuals with sporadic SCZ (188 subjects). Additional populations included autism spectrum disorder (142 subjects), nonsyndromic mental retardation (95 subjects), and control subjects (568 subjects). Functional validation of the human mutation was done in developing zebrafish. Here we report the identification of a de novo nonsense truncating mutation in one patient with SCZ, in kinesin 17, a synaptic motor protein. No de novo or truncating KIF17 mutations were found in the additional samples. We further validated the pathogenic nature of this mutation by knocking down its expression in zebrafish embryos, which resulted in a developmental defect. Together our findings suggest that disruption of KIF17, although rare, could result in a schizophrenia phenotype and emphasize the possible involvement of rare de novo mutations in this disorder.
... However, genes encoding proteins that contribute to neurogenesis, neurite formation and neuronal plasticity may affect not only the pathophysiology of schizophrenia, but also response or resistance to antipsychotics. [13][14][15][16][17] The gene encoding Disrupted in Schizophrenia 1 (DISC1) is a moderately conserved gene that codes for a 93.6-kDa protein of 854 amino acids with a globular N-terminus domain, a coiled C-terminus domain and several other functional domains. 18 The role of DISC1 is largely unknown, but these identified domains allow the DISC1 protein to interact with centrosomal and cytoskeletal proteins (NUDEL), neurodevelopmental regulators (NDE1/NDEL1 and FEZ1), neurosignalling regulators (PDE4B and PDE4D) and membrane-associated and signal transduction proteins such as activating transcription factor (ATF)4 and ATF5. ...
Article
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Three common missense variants of the Disrupted in Schizophrenia 1 (DISC1) gene, rs3738401 (Q264R), rs6675281 (L607F) and rs821616 (S704C), have been variably associated with the risk of schizophrenia. In a case-control study, we examine whether these gene variants are associated with schizophrenia and ultra-resistant schizophrenia (URS) in a population of French Caucasian patients. The URS phenotype is characterized according to stringent criteria as patients who experience no clinical, social and/or occupational remission in spite of treatment with clozapine and at least two periods of treatment with distinct conventional or atypical antipsychotic drugs. We find a significant association between DISC1 missense variants and URS. The association with rs3738401 remains significant after appropriate correction for multiple testing. These results suggest that the DISC1 rs3738401 missense variant is statistically linked with ultra-resistance to antipsychotic treatment.
... Reduced RELN expression due to epigenetic mechanisms is associated with schizophrenia and psychotic bipolar disorder (Impagnatiello et al., 1998;Guidotti et al., 2000;Eastwood and Harrison, 2003;Grayson et al., 2005;Herz and Chen, 2006). Genetic association studies also supported an association of RELN gene variants with treatment-resistant schizophrenia (Goldberger et al., 2005), particularly in women (Shifman et al., 2008). A recent study further suggested that allelic variants of RELN contribute to specific endophenotypes of schizophrenia such as working memory and executive functioning (Wedenoja et al., 2007). ...
Article
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The development of distinct cellular layers and precise synaptic circuits is essential for the formation of well functioning cortical structures in the mammalian brain. The extracellular protein Reelin, through the activation of a core signaling pathway, including the receptors ApoER2 and VLDLR (very low density lipoprotein receptor) and the adapter protein Dab1 (Disabled-1), controls the positioning of radially migrating principal neurons, promotes the extension of dendritic processes in immature forebrain neurons, and affects synaptic transmission. Here we report for the first time that the Reelin signaling pathway promotes the development of postsynaptic structures such as dendritic spines in hippocampal pyramidal neurons. Our data underscore the importance of Reelin as a factor that promotes the maturation of target neuronal populations and the development of excitatory circuits in the postnatal hippocampus. These findings may have implications for understanding the origin of cognitive disorders associated with Reelin deficiency.
... Third, the gene RELN, at 7q22, codes for the extracellular matrix protein reelin which is secreted by GABA-ergic interneurons, and its expression is regulated via promotor methylation by DNMT1, a methyltransferase 'imprinter' gene that may itself be subject to genomic conflicts over expression pattern Wilkins, 2005;Grayson et al., 2006). Reelin is dysregulated in both schizophrenia and autism, primarily via changes in its methylation status (Dong et al., 2005a;Fatemi, 2005;Fatemi et al., 2005;Grayson et al., 2005;Guidotti et al., 2005), and it has also been linked via genetic association studies with schizophrenia (Goldberger et al., 2005;Shifman et al., 2008) and autism (Persico et al., 2001;Zhang et al., 2002;Bonora et al., 2003;Devlin et al., 2004;Bartlett et al., 2005;Skaar et al., 2005;Serajee et al., 2006;Li et al., 2008). Three lines of evidence suggest imprinting effects in RELN expression: (1) the EICO database of potentially imprinted genes (Nikaido et al., 2004), (2) parent-of-origin effects in linkage of RELN with autism (Dutta et al., 2007;Rampersaud et al., 2007), and (3) studies of a mouse model for Turner syndrome in which RELN is differentially expressed between mice with a paternal versus maternal X chromosome (Davies et al., 2006); however, there is no direct evidence of imprinting for this gene. ...
Article
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I review and evaluate genetic and genomic evidence salient to the hypothesis that the development and evolution of psychotic spectrum conditions have been mediated in part by alterations of imprinted genes expressed in the brain. Evidence from the genetics and genomics of schizophrenia, bipolar disorder, major depression, Prader-Willi syndrome, Klinefelter syndrome, and other neurogenetic conditions support the hypothesis that the etiologies of psychotic spectrum conditions commonly involve genetic and epigenetic imbalances in the effects of imprinted genes, with a bias towards increased relative effects from imprinted genes with maternal expression or other genes favouring maternal interests. By contrast, autistic spectrum conditions, including Kanner autism, Asperger syndrome, Rett syndrome, Turner syndrome, Angelman syndrome, and Beckwith-Wiedemann syndrome, commonly engender increased relative effects from paternally expressed imprinted genes, or reduced effects from genes favouring maternal interests. Imprinted-gene effects on the etiologies of autistic and psychotic spectrum conditions parallel the diametric effects of imprinted genes in placental and foetal development, in that psychotic spectrum conditions tend to be associated with undergrowth and relatively-slow brain development, whereas some autistic spectrum conditions involve brain and body overgrowth, especially in foetal development and early childhood. An important role for imprinted genes in the etiologies of psychotic and autistic spectrum conditions is consistent with neurodevelopmental models of these disorders, and with predictions from the conflict theory of genomic imprinting.
... The report of decreased levels of reelin in the brain and plasma of autistic patients [Fatemi et al., 2001[Fatemi et al., , 2002 highlights the role of reelin in this disorder but it is not confined to autism alone as it has been implicated in other neurodevelopmental disorders, such as autosomal recessive lissencephaly syndrome [Hong et al., 2000] and schizophrenia [Impagnatiello et al., 1998;Akahane et al., 2002;Chen et al., 2002a;Goldberger et al., 2005]. Till date, several association studies have been carried out on reelin as a candidate gene for autism. ...
Article
Autism is a neurodevelopmental disorder with high heritability factor and the reelin gene, which codes for an extracellular matrix protein involved with neuronal migration and lamination is being investigated as a positional and functional candidate gene for autism. It is located on chromosome 7q22 within the autism susceptible locus (AUTS1); identified in earlier genome scans and several investigations have been carried out on various ethnic groups to assess possible association and linkage of the gene with autism. However, the findings are still inconclusive. In the present study which represents the first report of such a study on the Indian population, genotyping analyses of CGG repeat polymorphism at 5'UTR, two single nucleotide polymorphisms (SNP) at exon 6 and exon 50 were performed in 73 autistic subjects, 129 parents, and 80 controls. The allelic distributions of the repeat polymorphism and exon 50 T/C SNP were quite different from earlier reports in other populations. Allelic and genotypic distribution of the markers did not show any differences between the cases and controls. While our preliminary data on family-based association studies on 58 trios showed no preferential transmission of any allele from the parents to the affected offspring, TDT and HHRR analyses revealed significant paternal transmission distortions for 10- and > or =11-repeat alleles of CGG repeat polymorphism. Thus, the present study suggests that 5'UTR of reelin gene may have a role in the susceptibility towards autism with the paternal transmission and non-transmission respectively of 10- and > or =11-repeat alleles, to the affected offspring.
... It is important to highlight that in recent years it has been described functional SNPs in these genes [57][58][59][60][61][62][63]. Preliminary work, based in other formal hypothesis, shows that this association between polymorphisms in synaptic genes and AD may be possible [64], as it has been demonstrated in other neuropsychiatric diseases [65][66][67][68]. A "synaptogenomics" approach may be important to discover genetic correlates of this neurodegenerative synaptopathy. ...
Article
In this paper, we review experimental advances in molecular neurobiology of Alzheimer's disease (AD), with special emphasis on analysis of neural function of proteins involved in AD pathogenesis, their relation with several signaling pathways and with oxidative stress in neurons. Molecular genetic studies have found that mutations in APP, PS1 and PS2 genes and polymorphisms in APOE gene are implicated in AD pathogenesis. Recent studies show that these proteins, in addition to its role in beta-amyloid processing, are involved in several neuroplasticity-signaling pathways (NMDA-PKA-CREB-BDNF, reelin, wingless, notch, among others). Genomic and proteomic studies show early synaptic protein alterations in AD brains and animal models. DNA damage caused by oxidative stress is not completely repaired in neurons and is accumulated in the genes of synaptic proteins. Several functional SNPs in synaptic genes may be interesting candidates to explore in AD as genetic correlates of this synaptopathy in a "synaptogenomics" approach. Thus, experimental evidence shows that proteins implicated in AD pathogenesis have differential roles in several signaling pathways related to neuromodulation and neurotransmission in adult and developing brain. Genomic and proteomic studies support these results. We suggest that oxidative stress effects on DNA and inherited variations in synaptic genes may explain in part the synaptic dysfunction seen in AD.
... 48 The long arms of chromosome 7 have also gained strong evidence for association with schizophrenia. 10 Genetic evidence for linkage also exists for the reelin gene (RELN), which is involved in neuronal migration, axonal branching and in a signaling pathway that underlies memory formation and synaptic connectivity; 49,50 however, the support is not strong. 51 Promising data for the gene encoding metabotropic glutamate receptor type 3, which is located on 7q21.1-q21.2 and is associated with prefrontal function, 52 supports the possibility of this gene being etiologically implicated in schizophrenia, but the evidence remains weak. ...
Article
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Schizophrenia is a serious and disabling mental disorder with symptoms such as auditory hallucinations, disordered thinking and delusions, avolition, anhedonia, blunted affect and apathy. In this review article we seek to present the current scientific findings from linkage studies and susceptible genes and the pathophysiology of white matter in schizophrenia. The article has been reviewed in two parts. The first part deals with the linkage studies and susceptible genes in schizophrenia in order to have a clear-cut picture of the involvement of chromosomes and their genes in schizophrenia. The genetic linkage results seem to be replicated in some cases but in others are not. From these results, we cannot draw a fine map to a single locus or gene, leading to the conclusion that schizophrenia is not caused by a single factor/gene. In the second part of the article we present the oligodendrocyte-related genes that are associated with schizophrenia, as we hypothesize a potential role of oligodendrocyte-related genes in the pathology of the disorder.
... We also found no evidence for stratification in the Ashkenazi sample, indicating that the increase in allele frequency observed in women with schizophrenia cannot be caused by population structure in the Ashkenazi Jewish sample. Genetic association studies have so far failed to report any consistent association between Reelin gene polymorphisms and schizophrenia2324252627. However the gene has not so far been systematically screened. ...
Article
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Author Summary Schizophrenia is a complex mental disease, which includes symptoms of delusions, hallucinations, disorganized speech, aberrant behavior, lack of emotional expression, diminished motivation, and social withdrawal. The cause of schizophrenia is unknown, but there is extensive evidence that genetics play a significant role in its aetiology. We studied the genetic basis of schizophrenia by analyzing around 500,000 genetic variants distributed across the whole human genome in DNA from schizophrenic patients and controls. We analyzed separately the DNA from men and women, and identified a genetic variant that increases the risk of developing schizophrenia in women only. The genetic variant is estimated to increase the risk of schizophrenia for women carrying the risk variant by 1.4-fold. The genetic variant is in a gene called reelin, which is known to play a part in brain development. However, it is still unclear how this genetic variant predisposes to schizophrenia nor why it is specific to women only.
... To the best of our knowledge, the current study is the first SZ association study with such a large sample set, as well as the first using a gene-wide approach, when investigating variations in the large RELN gene, which spans 517.7 kbp and harbors 65 exons [Chen et al., 2002b]. Three previous publications have investigated if a polymorphic GGC repeat in the RELN 5 0 UTR [Akahane et al., 2002; Goldberger et al., 2005; Huang and Chen, 2006], reported to be associated with autism [Persico et al., 2001] and regulate RELN expression [Persico et al., 2006], is associated with SZ. All studies presented negative findings, but the sample sizes were small. ...
Article
Several lines of evidence support the theory of schizophrenia (SZ) being a neurodevelopmental disorder. The structural, cytoarchitectural and functional brain abnormalities reported in patients with SZ, might be due to aberrant neuronal migration, since the final position of neurons affects neuronal function, morphology, and formation of synaptic connections. We have investigated the putative association between SZ and gene variants engaged in the neuronal migration process, by performing an association study on 839 cases and 1,473 controls of Scandinavian origin. Using a gene-wide approach, tagSNPs in 18 candidate genes have been genotyped, with gene products involved in the neuron-to-glial cell adhesion, interactions with the DISC1 protein and/or rearrangements of the cytoskeleton. Of the 289 markers tested, 19 markers located in genes MDGA1, RELN, ITGA3, DLX1, SPARCL1, and ASTN1, attained nominal significant P-values (P < 0.05) in either a genotypic or allelic association test. All of these genes, except transcription factor DLX1, are involved in the adhesion between neurons and radial glial cells. Eight markers obtained nominal significance in both tests, and were located in intronic or 3'UTR regions of adhesion molecule MDGA1 and previously reported SZ candidate RELN. The most significant result was attained for MDGA1 SNP rs9462341 (unadjusted association results: genotypic P = 0.00095; allelic P = 0.010). Several haplotypes within MDGA1, RELN, ITGA3, and ENAH were nominally significant. Further studies in independent samples are needed, including upcoming genome wide association study results, but our data suggest that MDGA1 is a new SZ susceptibility gene, and that altered neuronal migration is involved in SZ pathology.
... The view that schizophrenia is a neurodevelopmental disorder is not uniformly accepted and schizophrenia does not have the characteristics of a classical developmental disorder. However, if schizophrenia and related disorders do have a neurodevelopmental component, due in part to both inherited genomic alterations in DISC1, dysbindin and COMT (Gornick et al, 2005), and epigenetic genomic alterations in reelin and GABAergic neuronal markers (Dong et al, 2005; Goldberger et al, 2005; Grayson et al, 2005), effective treatment strategies should target the underlying deficits. If the underlying defect is principally due to developmentally encoded deficits in microcircuitry, then obvious pharmacological strategies would be to ameliorate these deficits (see below for examples). ...
Article
Despite significant progress in understanding the biological systems and mechanisms involved in CNS disorders, use of this knowledge to realize practical gains in psychiatric care has been slow. To gain further insight into the reasons for failure and success in CNS drug discovery, preclinical predictors of success and failure for CNS drug discovery were evaluated for drugs developed for schizophrenia, depression, and anxiety. Specifically, we examined the success rate for drugs that had entered at least the later stages of preclinical research. Almost 500 compounds (140 antipsychotic; 211 antidepressant; 143 anxiolytic) were classified based on their molecular target(s) and evaluated based on preclinical validation, whether preclinical studies predicted clinical efficacy, and whether the compound displayed greater efficacy than ‘conventional treatment’ Results varied with indication but suggest that preclinical models have modest to good ability to predict overall clinical efficacy and adverse effect liability but are less able to predict efficacy greater than conventional treatment. In order to fully realize the potential therapeutic impact of recent basic science discoveries, it will be critical to increase attention on rigorous target validation at each step of the drug discovery process and focus efforts on developing new tools and clinical models that can be used for proof-of-concept studies in early clinical development. Also, increased attention should be focused on the development of early predictors of adverse effects of candidate compounds.
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However, there is strong belief that further search for genetic factors underlying treatment response, which are also defined as “treatment biomarkers,” would contribute to the personalized medicine approach, in which biomarkers would guide decision-making and help to select the most suitable medication for individual patients. Moreover, incorporation of genetic factors into treatment algorithms could speed recovery from disease by shortening or eliminating lengthy and ineffective trials and thus reduce the risk of treatment resistance. In this chapter, we review the current state of pharmacogenomics of several mental health disorders including latest results from candidate genes and genome-wide association studies. Although a host of genes has been explored in psychiatry, only small numbers of replicated findings have emerged so far. The sample sizes and heterogeneous phenotype definition may be considered the major impediments to success in this important field.
Article
Previous studies (including genome-wide association study (GWAS) and candidate gene studies) have revealed the important roles of genetic risk factors in schizophrenia, and RELN has been identified as a risk gene for this illness. We recently found that the low-density lipoprotein receptor-related protein 8 (LRP8), a receptor of Reelin (the protein encoded by RELN), was significantly associated with schizophrenia and bipolar disorder in European populations. To further enhance our understanding of its role in the risk of psychiatric illnesses, we conducted meta-analyses of a higher density of single nucleotide polymorphisms (SNPs, N = 173) in LRP8 to understand their associations with schizophrenia in much larger samples (39,400 cases and 50,357 controls) from populations of European, Chinese and African American ancestries. The significant risk SNPs then underwent further analyses to understand their correlations with bipolar disorder and anxiety disorders, as well as LRP8 expression. We observed that rs5177 in the 3′ untranslated region (3’UTR) of LRP8 was associated with schizophrenia and other psychiatric disorders, and rs5177 was also associated with LRP8 mRNA expression. These data further support LRP8 as a schizophrenia susceptibility gene, and suggest that this variant is likely a risk locus in general populations.
Article
New neurons are generated throughout adulthood in two regions of the brain, the olfactory bulb and dentate gyrus of the hippocampus, and are incorporated into the hippocampal network circuitry; disruption of this process has been postulated to contribute to neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. Known modulators of adult neurogenesis include signal transduction pathways, the vascular and immune systems, metabolic factors, and epigenetic regulation. Multiple intrinsic and extrinsic factors such as neurotrophic factors, transcription factors, and cell cycle regulators control neural stem cell proliferation, maintenance in the adult neurogenic niche, and differentiation into mature neurons; these factors act in networks of signaling molecules that influence each other during construction and maintenance of neural circuits, and in turn contribute to learning and memory. The immune system and vascular system are necessary for neuronal formation and neural stem cell fate determination. Inflammatory cytokines regulate adult neurogenesis in response to immune system activation, whereas the vasculature regulates the neural stem cell niche. Vasculature, immune/support cell populations (microglia/astrocytes), adhesion molecules, growth factors, and the extracellular matrix also provide a homing environment for neural stem cells. Epigenetic changes during hippocampal neurogenesis also impact memory and learning. Some genetic variations in neurogenesis related genes may play important roles in the alteration of neural stem cells differentiation into new born neurons during adult neurogenesis, with important therapeutic implications. In this review, we discuss mechanisms of and interactions between these modulators of adult neurogenesis, as well as implications for neurodegenerative disease and current therapeutic research.
Article
Reelin-Dab1 signaling is involved in brain development and neuronal functions. The abnormalities in the signaling through either reduction of Reelin and Dab1 gene expressions or the genomic mutations in the brain have been reported to be associated with psychiatric disorders. However, it has not been clear if the deficiency in Reelin-Dab1 signaling is responsible for symptoms of the disorders. Here, to examine the function of Reelin-Dab1 signaling in the forebrain, we generated dorsal forebrain-specific Dab1 conditional knockout mouse (Dab1 cKO) and performed a behavioral test battery on the Dab1 cKO mice. Although conventional Dab1 null mutant mice exhibit cerebellar atrophy and cerebellar ataxia, the Dab1 cKO mice had normal cerebellum and showed no motor dysfunction. Dab1 cKO mice exhibited behavioral abnormalities, including hyperactivity, decreased anxiety-like behavior, and impairment of working memory, which are reminiscent of symptoms observed in patients with psychiatric disorders such as schizophrenia and bipolar disorder. These results suggest that deficiency of Reelin-Dab1 signal in the dorsal forebrain is involved in the pathogenesis of some symptoms of human psychiatric disorders.
Article
More than 40 years of research have convincingly demonstrated that the adult mammalian brain is capable to generate new neurons from neuronal stem cells. This process, which also occurs in humans, has been termed "adult neurogenesis" (AN) and takes place in the dentate gyrus of the hippocampus and the subventricular zone. Its function however remains elusive; as stress decreases and antidepressant treatment increases AN in animal studies, a role for AN in the pathogenesis of depression has been proposed. This nevertheless has been recently questioned, as human studies did not find lower rates of neural stem cell proliferation in affective disorders. However, decreased AN was demonstrated in schizophrenia. Given the functions of the hippocampus, disordered AN might contribute to cognitive deficits in schizophrenia, but also to the development of delusional reality perception. Neuroimaging as well as animal studies further support the notion of disturbed AN in schizophrenia, as e.g. mice deficient in reelin or NPAS3 feature behavioural abnormalities reminiscent of schizophrenia together with disturbed AN. Furthermore, human case-control studies demonstrate an association of genes, which regulate AN levels, with schizophrenia; those include BDNF, DISC1, and - again - NPAS3. Together, several lines of evidence thus argue for an involvement of AN in the pathogenesis of schizophrenia.
Article
Studies have suggested that reelin (RELN) polymorphism was associated with the susceptibility of Schizophrenia (SZ), but the results remained controversial. Thus, we conducted this meta-analysis to determine whether RELN variants (rs7341475 and rs262355) were associated with SZ risk. Studies were identified through retrieving Web of Science, PubMed and Embase databases from inception to May 2015. The genotype data were extracted to calculate the odds ratios (ORs) and 95% confidence intervals (CIs). For rs7341475, five studies with 4741 SZ patients and 10075 controls are included and the results indicate that carriage of A allele is associated with decreased SZ risk in dominant genetic model (OR=0.90, 95%CI = 0.83-0.98) and additive model (OR=0.90, 95% CI=0.84-0.97). Subgroup analysis indicates that the association between rs7341475 and SZ is only significant in Caucasian. For rs262355, four studies with 2017 SZ patients and 3274 controls are included, the results demonstrate that carriage of A allele is associated with increased risk of SZ only in Caucasian (dominant model: OR=1.17, 95%CI=1.01-1.37; additive model OR=1.13, 95%CI = 1.02-1.27). This meta-analysis suggests that rs7341475 (A/G) and rs262355 (A/T) polymorphisms in RELN gene are inversely associated with SZ risk.
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Glutamatergic and GABAergic neuropathology in schizophrenia Psychopharmacology and physiology of glutamate and GABA systems Implications Acknowledgements References
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Studies from several laboratories have provided convincing data to support the notion that altered DNA methylation in response to varying physiological and environmental conditions may play a critical role in the fine-tuning of gene expression. However, the establishment of abnormal gene promoter DNA methylation patterns resulting from environmental insults or dysfunctional genes of the DNA methylation machinery may destabilize the normal epigenetic modification of genes. This may affect the equilibrium in the differential gene expression patterns in the normal differentiated cells and tilt the balance toward the disease phenotype. The individuals with genetic susceptibility to specific diseases are likely to be more prone to abnormal DNA methylation. Thus, it is highly likely that the lack of a direct relationship between genotype and phenotype in major psychiatric disorders and the variability in the manifestation of diseases in individuals with identical genetic makeup could be derived from the changes in the DNA methylation patterns.
Article
Our previous neurocognitive studies of schizophrenia outlined two clusters of affected subjects--cognitively spared (CS) and cognitive deficit (CD), the latter's characteristics pointing to developmental origins and impaired synaptic plasticity. Here we investigate the contribution of polymorphisms in major regulators of these processes to susceptibility to schizophrenia and to CD in patients. We examine variation in genes encoding proteins at the gateway of Reelin signaling: ligands RELN and APOE, their common receptors APOER2 and VLDLR, and adaptor DAB1. Association analysis with disease outcome and cognitive performance in the Western Australian Family Study of Schizophrenia (WAFSS) was followed by replication analysis in the Australian Schizophrenia Research Bank (ASRB) and in the Health in Men Study (HIMS) of normal aging males. In the WAFSS sample, we observed significant association of APOE, APOER2, VLDLR, and DAB1 SNPs with disease outcome in the case-control and CD-control datasets, and with pre-morbid intelligence and verbal memory in cases. HIMS replication analysis supported rs439401 (APOE regulatory region), and rs2297660 and rs3737983 (APOER2), with an effect on memory performance in normal aging subjects consistent with the findings in schizophrenia cases. APOER2 gene expression analysis revealed lower transcript levels in lymphoblastoid cells from cognitively impaired schizophrenia patients of the alternatively spliced exon 19, mediating Reelin signaling and synaptic plasticity in the adult brain. ASRB replication analysis produced marginally significant results, possibly reflecting a recruitment strategy biased toward CS patients. The data suggest a contribution of neurodevelopmental/synaptic plasticity genes to cognitive impairment in schizophrenia.
Article
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Production and function of natural antibodies (NAbs) constitutes an important mechanism of the humoral innate immunity in vertebrates. The level of NAbs in chicken is heritable and the genetic background has been partly investigated. However, to date the genetic determination of humoral innate immune response in avian species has not been fully described. The goal of this study was to propose a new set of candidate genes with a potential effect on the NAb phenotype for further SNP association study. In silico analysis of positional and functional candidate genes covered 14 QTL regions associated with LPS, LTA & KLH NAbs and located on six chromosomes: GGA5, GGA6, GGA9, GGA14, GGA18 and GGAZ. The function of the genes was subsequently determined based on the NCBI, KEGG, Gene Ontology and InnateDB databases. As a result, the core panel of 38 genes participating in metabolic pathways of innate immune response was proposed. Most of them were assigned to chromosomes: GGA14, GGA5, GGA6 and GGAZ (13, 9, 8 and 5 genes, respectively). These candidate genes encode proteins predicted to play a role in (i) proliferation, differentiation and function of B lymphocytes; (ii) TLR signalling pathway, and (iii) MAP signalling cascade. Proposed set of candidate genes is recommended to be included in the follow-up studies to model genetic networks of innate humoral immune response in chicken.
Article
Schizophrenia (SZ) is a common and complex psychiatric disorder with a strong genetic component. Previous research suggests that mutations altering genes in neurodevelopmental pathways contribute to SZ. Reelin gene (RELN) maps to chromosome 7q22.1, the encoded protein plays a pivotal role in guiding neuronal migration, lamination and connection during embryonic brain development. Several reports had indicated that reduced RELN expression is associated with human mental illnesses such as SZ, mood disorders and autism. In this study, case-control association analyses were performed in the Han Chinese population to determine if the RELN gene is a susceptibility gene for SZ. Thirty-seven single nucleotide polymorphisms (SNPs) were genotyped in 528 paranoid SZ patients and 528 control subjects. A significant association was found between rs12705169 and SZ (p=0.001). Moreover, the haplotypes constructed from five SNPs showed significant differences between cases and controls (p=0.041). When subjects were divided by gender, rs12705169 remained significant difference only in females (OR=0.24, 95%CI=0.14-0.40 for CC and OR=0.40, 95%CI=0.27-0.58 for AC), both in the allele and genotype (p=0.0001 for both). This study describes a positive association between RELN and SZ in the Han Chinese population, and provides genetic evidence to support the gender difference of SZ.
Article
A recent genome-wide association study linked a common variant in RELN (rs7341475G) with risk for schizophrenia in women. In the largest neuroimaging intermediate phenotype study reported so far, we evaluated the effect of rs7341475 on an extended array of different neuroscientific measures. Brain structure was evaluated with voxel-based morphometry and diffusion tensor imaging. Brain function during working memory was examined with functional magnetic resonance imaging. The RELN expression was determined in postmortem brain tissue of the dorsolateral prefrontal cortex and hippocampus. A total of 736 datasets were examined (voxel-based morphometry: n = 230, diffusion tensor imaging: n = 93, functional magnetic resonance imaging: n = 308, RELN expression: n = 105). Our analyses did not provide evidence for a significant main effect of gene or gene x sex interaction effect on any of the examined measures. This study does not suggest a significant impact of rs7341475 on brain structure, function, and RELN expression, arguing that this single nucleotide polymorphism and others linked with it do not affect brain measures related to the biology of schizophrenia.
Article
Reelin is a conserved extracellular glycoprotein crucial for neurodevelopment. In adulthood, Reelin is an important modulator of NMDA receptor-mediated neurotransmission, required for synaptic plasticity, learning and memory. Consequently, abnormal Reelin-mediated signaling has been associated with many human brain disorders involving directly or indirectly altered NMDA receptor function. For most neurological and neuropsychiatric disorders, abnormalities during brain development appear central in the disease etiology. However, a similar causative relationship for neurodegenerative diseases, like Alzheimer's disease (AD), has not been investigated yet.
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The challenges in gene identification for psychiatric disorders have awakened interest toward quantitative traits and endophenotypes that are potentially more closely related to the underlying biology and provide more power in the linkage and association analyses. Previously, we successfully replicated schizophrenia linkage on chromosome 7q21-32 in Finnish families and demonstrated that an intragenic short tandem repeat (STR) allele of the regional Reelin (RELN) gene is associated with multiple cognitive traits representing central cognitive functions regarded as valid endophenotypes for schizophrenia. Here, we used an extended sample of 290 Finnish families with schizophrenia and 375 control subjects in an association analysis between 96 SNPs and three STRs in RELN and diagnostic categories, clinical disorder features, as well as central cognitive functions impaired in schizophrenia. We replicated the original association between RELN intragenic STR allele and working memory in individuals (n = 342) not overlapping with the previous study. This risk allele remained central in the whole study sample by being associated with impaired cognitive functioning and more severe positive and negative symptoms of schizophrenia (p = .0005-.00002). Additionally, multiple SNPs indicated association with the severity of positive symptoms of schizophrenia and together showed potential additive effect on the severity of the symptoms (p = .0000001). However, no significant associations with clinical diagnostic categories emerged. The strongest effects on cognitive functions were detected among the affected individuals. We thus propose a particular role for RELN as a modifier gene of the pathogenesis of schizophrenia.
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The association of the histone deacetylase (HDAC) inhibitor valproate (VPA) with atypical antipsychotics has become a frequent treatment strategy for schizophrenia and bipolar disorder. Because the VPA doses administered are elevated, one cannot assume that the benefits of the VPA plus antipsychotic treatment are exclusively related to the covalent modifications of nucleosomal histone tails. We compared the actions of N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)aminomethyl]benzamide derivative (MS-275), which is a potent HDAC inhibitor in vitro, with the actions of VPA for their ability to (i) increase the acetylated status of brain nucleosomal histone tail domains and (ii) to regulate brain histone-RELN and histone-GAD(67) promoter interactions. MS-275 increases the content of acetylhistone 3 (Ac-H3) in the frontal cortex. Whereas this response peaks after a s.c. injection of 15 micromol/kg, the increase in Ac-H3 content in the hippocampus becomes significant only after an injection of 60 micromol/kg, suggesting that MS-275 is 30- to 100-fold more potent than VPA in increasing Ac-H3 in these brain regions. In contrast to VPA, MS-275, in doses up to 120 micromol/kg, fails to increase Ac-H3 content in the striatum. Chromatin immunoprecipitation shows that MS-275 increases Ac-H3-RELN and Ac-H3-GAD(67) promoter interaction in the frontal cortex. These results suggest that MS-275 is a potent brain region-selective HDAC inhibitor. It is likely that, in addition to MS-275, other benzamide derivatives, such as sulpiride, are brain-region selective inhibitors of HDACs. Hence, some benzamide derivatives may express a greater efficacy than VPA as an adjunctive to antipsychotics in the treatment of epigenetically induced psychiatric disorders.
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Neurodevelopmental changes may underlie the brain dysfunction seen in schizophrenia. While advances have been made in our understanding of the genetics of schizophrenia, little is known about how non-genetic factors interact with genes for schizophrenia. The present analysis of genes potentially associated with schizophrenia is based on the observation that hypoxia prevails in the embryonic and fetal brain, and that interactions between neuronal genes, molecular regulators of hypoxia, such as hypoxia-inducible factor 1 (HIF-1), and intrinsic hypoxia occur in the developing brain and may create the conditions for complex changes in neurodevelopment. Consequently, we searched the literature for currently hypothesized candidate genes for susceptibility to schizophrenia that may be subject to ischemia-hypoxia regulation and/or associated with vascular expression. Genes were considered when at least two independent reports of a significant association with schizophrenia had appeared in the literature. The analysis showed that more than 50% of these genes, particularly AKT1, BDNF, CAPON, CCKAR, CHRNA7, CNR1, COMT, DNTBP1, GAD1, GRM3, IL10, MLC1, NOTCH4, NRG1, NR4A2/NURR1, PRODH, RELN, RGS4, RTN4/NOGO and TNF, are subject to regulation by hypoxia and/or are expressed in the vasculature. Future studies of genes proposed as candidates for susceptibility to schizophrenia should include their possible regulation by physiological or pathological hypoxia during development as well as their potential role in cerebral vascular function.
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Reelin, a large glycoprotein secreted by telencephalic GABAergic neurons, plays an important role in neuronal guidance embryonically and in synaptic plasticity postnatally. The reeler heterozygous mouse (+/rl) appears superficially normal but has been of interest as an animal model for psychosis since the discovery that reelin is 50% down-regulated in postmortem psychotic brain. Brain abnormalities in +/rl are similar to psychotic brain and include a reduction in glutamic acid de carboxylase 67 (GAD67), dendritic arbors and spine density in cortex and hippocampus, and abnormalities in synaptic function including long-term potentiation (LTP). In spite of these abnormalities, behavioral abnormalities in +/rl are subtle and controversial. Recent findings indicate that the reelin (RELN) and GAD67 promoters are hypermethylated in GABAergic neurons of psychotic postmortem brain and that DNA methyltransferase 1 (DNMT1) is up-regulated. Hypermethlyation of RELN and GAD67 promoters can be induced by treating mice with methionine, and these mice display brain and behavioral abnormalities similar to +/rl. Thus, an animal model that combines genetic heterozygocity with epigenesis holds promise for understanding the role of Reelin down-regulation in psychosis.
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Adult neurogenesis is one of the most rapidly growing areas in neuroscience research and there is great interest in its potential role in the pathophysiology of psychiatric illness. In parallel with early development, adult neurogenesis occurs through the proliferation of precursor cells which migrate to specific regions and differentiate into neurons with characteristics indistinguishable from existing mature neurons. These findings have led to the re-definition of the concept of network plasticity in the adult brain, to include the formation of new neurons as well as new connections. This review examines the idea that adult neurogenesis may be disturbed in schizophrenia. We discuss evidence for abnormal mechanisms of neurogenesis and expression of developmental genes in schizophrenia, the influence of antipsychotic drugs on neurogenesis and the role of candidate schizophrenia susceptibility genes in adult neurogenesis. The recent discovery of molecular markers transiently expressed in newborn neurons within adult neurogenic brain regions could be used to probe whether neurogenesis is disturbed in schizophrenia. Adult neurogenesis could also be used as a unique tool for investigating genes involved in early brain development using post-mortem brains. This is particularly relevant for brain disorders with developmental origins such as schizophrenia.
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This article reviews the antidepressant actions of ketamine, an N-methyl-D-aspartame glutamate receptor (NMDAR) antagonist, and offers a potential neural mechanism for intranasal ketamine's ultra-rapid actions based on the key role of NMDAR in the nonhuman primate prefrontal cortex (PFC). Although intravenous ketamine infusions can lift mood within hours, the current review describes how intranasal ketamine administration can have ultra-rapid antidepressant effects, beginning within minutes (5–40 minutes) and lasting hours, but with repeated treatments needed for sustained antidepressant actions. Research in rodents suggests that increased synaptogenesis in PFC may contribute to the prolonged benefit of ketamine administration, beginning hours after administration. However, these data cannot explain the relief that occurs within minutes of intranasal ketamine delivery. We hypothesize that the ultra-rapid effects of intranasal administration in humans may be due to ketamine blocking the NMDAR circuits that generate the emotional representations of pain (eg, Brodmann Areas 24 and 25, insular cortex), cortical areas that can be overactive in depression and which sit above the nasal epithelium. In contrast, NMDAR blockade in the dorsolateral PFC following systemic administration of ketamine may contribute to cognitive deficits. This novel view may help to explain how intravenous ketamine can treat the symptoms of depression yet worsen the symptoms of schizophrenia.
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The influence of chronic electroconvulsive seizure (ECS) or antidepressant drug treatments on expression of brain-derived neurotrophic factor (BDNF) and its receptor, trkB, was examined by in situ hybridization and Northern blot. In frontal cortex, acute ECS increased BDNF mRNA approximately twofold, an effect significantly augmented by a prior course of chronic ECS treatment (10 d). In the hippocampus, the influence of chronic ECS varied between the major subfields. In the dentate gyrus granule cell layer, chronic ECS decreased the acute induction of BDNF and trkB mRNA by approximately 50%, but prolonged their expression: levels remained elevated two- to threefold 18 hr later after the last chronic ECS treatment, but returned to control 18 hr after acute ECS. In CA3 and CA1 pyramidal cell layers, chronic ECS significantly elevated the acute induction of BDNF, and tended to prolong the expression of BDNF and trkB mRNA. A similar effect was observed in layer 2 of the piriform cortex, where chronic ECS significantly increased the acute induction and prolonged the expression of BDNF and trkB mRNA. Chronic (21 d), but not acute (1 d), administration of several different antidepressant drugs, including tranylcypromine, sertraline, desipramine, or mianserin, significantly increased BDNF mRNA and all but mianserin increased trkB mRNA in hippocampus. In contrast, chronic administration of nonantidepressant psychotropic drugs, including morphine, cocaine, or haloperidol, did not increase levels of BDNF mRNA. Furthermore, chronic administration of ECS or antidepressant drugs completely blocked the down-regulation of BDNF mRNA in the hippocampus in response to restraint stress. The enhanced induction and prolonged expression of BDNF in response to chronic ECS and antidepressant drug treatments could promote neuronal survival, and protect neurons from the damaging effects of stress.
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The mouse reelin gene (Reln) encodes a novel protein that, when mutated, results in the characteristic reeler phenotype. A key component of this phenotype is the extensive disruption of the organization of many brain structures. Reelin is believed to be an extracellular protein that controls neural cell positioning during brain development. The reelin gene is conserved in many vertebrate species, including humans. To study the role of the reelin homolog in human brain development, we have isolated and characterized the human gene (RELN). Like its murine counterpart, RELN is large, encoding an mRNA of approximately 12 kb. Overlapping cDNA clones containing the entire open reading frame were isolated and sequenced, revealing that the predicted mouse and human proteins are similar in size (388 kD) and that the amino acid and nucleotide sequences are 94.2% and 87.2% identical, respectively. Northern hybridization analyses revealed that RELN is expressed in fetal and postnatal brain as well as liver. The expression of RELN in postnatal human brain was high in the cerebellum. RELN was mapped to human chromosome 7q22, based on both fluorescence in situ hybridization studies and localization within a well-positioned yeast artificial chromosome (YAC) contig. The YAC contig also contains a number of gentic markers. Together, these studies provide the sequence information and genetic tools for performing more detailed analyses of RELN in an attempt to define its role in human brain development and possibly in human disease.
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We report the results of a four-stage genome-wide scan in a schizophrenia study sample consisting of 134 affected sib-pairs collected in Finland. In stage I we genotyped 370 markers from the Weber 6 screening set ( N = 52 affected sib-pairs); in stage II we followed up 40 markers by typing first-degree relatives of the sib-pairs; in stage III we genotyped 15 markers in 134 families; and in stage IV we genotyped a denser marker map in the two most promising regions, one on chromosome 1 and another on chromosome 7, in all families. Diagnoses were based on three nationwide health care registers and consensus diagnosis based on review of all medical records. The most significant finding was a two-point lod score of 3.18 with marker D7S486 using a dominant model and treating all individuals with either schizophrenia, schizoaffective disorder or other schizophrenia spectrum disorder as affected. Multipoint analysis with MAPMAKER/SIBS resulted in a MLS of 3.53 between markers D7S501 and D7S523 using the broadest diagnostic model, including major depressive disorder and bipolar type I as affecteds in addition to the aforementioned phenotypes. These results were obtained by including in the analyses only individuals from the late settlement region of Finland settled in the 16th century. Additionally, some support was obtained for linkage to chromosome 1, in a region previously identified in a genome-wide scan of a study sample from a sub-isolate of Finland. Our data demonstrate the importance of genealogical information for studies aiming at identification of predisposing loci in complex diseases.
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Schizophrenia is a heterogeneous disease involving genetic and environmental factors. The frequency of structural brain abnormalities or physical anomalies supports a neurodevelopmental etiology, especially in early onset schizophrenia. Brain-Derived-Neurotrophic-Factor (BDNF) is involved in the neurodevelopment of dopaminergic (DA)-related systems and interacts with the meso-limbic DA systems, involved in the therapeutic response to antipsychotic drugs and substance abuse. In addition, BDNF promotes and maintains dopamine D3 receptor (DRD3) expression. In a French Caucasian population, we found no statistical difference in allele or genotype distribution of the BDNF gene dinucleotide repeat polymorphism (166-174 bp) between the whole group of schizophrenic patients and controls. By contrast, an excess of the 172-176 bp alleles was found in patients with late onset, in neuroleptic-responding patients and in non-substance-abusing patients. BDNF gene variants thus appear to be associated with developmental features of schizophrenia. In addition, this association with good treatment responding was independent from the association found with the DRD3 Ball gene polymorphism in the same population. These results suggest an independent contribution of each gene to a treatment-sensitive form of schizophrenia.
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Reelin (RELN) is a glycoprotein secreted preferentially by cortical gamma-aminobutyric acid-ergic (GABAergic) interneurons (layers I and II) that binds to integrin receptors located on dendritic spines of pyramidal neurons or on GABAergic interneurons of layers III through V expressing the disabled-1 gene product (DAB1), a cytosolic adaptor protein that mediates RELN action. To replicate earlier findings that RELN and glutamic acid decarboxylase (GAD)(67), but not DAB1 expression, are down-regulated in schizophrenic brains, and to verify whether other psychiatric disorders express similar deficits, we analyzed, blind, an entirely new cohort of 60 postmortem brains, including equal numbers of patients matched for schizophrenia, unipolar depression, and bipolar disorder with nonpsychiatric subjects. Reelin, GAD(65), GAD(67), DAB1, and neuron-specific-enolase messenger RNAs (mRNAs) and respective proteins were measured with quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) or Western blot analyses. Reelin-positive neurons were identified by immunohistochemistry using a monoclonal antibody. Prefrontal cortex and cerebellar expression of RELN mRNA, GAD(67) protein and mRNA, and prefrontal cortex RELN-positive cells was significantly decreased by 30% to 50% in patients with schizophrenia or bipolar disorder with psychosis, but not in those with unipolar depression without psychosis when compared with nonpsychiatric subjects. Group differences were absent for DAB1,GAD(65) and neuron-specific-enolase expression implying that RELN and GAD(67) down-regulations were unrelated to neuronal damage. Reelin and GAD(67) were also unrelated to postmortem intervals, dose, duration, or presence of antipsychotic medication. The selective down-regulation of RELN and GAD(67) in prefrontal cortex of patients with schizophrenia and bipolar disorder who have psychosis is consistent with the hypothesis that these parameters are vulnerability factors in psychosis; this plus the loss of the correlation between these 2 parameters that exists in nonpsychotic subjects support the hypothesis that these changes may be liability factors underlying psychosis.
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Accumulation of neurobiological knowledge points to neurodevelopmental origins for certain psychotic and mood disorders. Recent landmark postmortem reports implicate Reelin, a secretory glycoprotein responsible for normal lamination of brain, in the pathology of schizophrenia and bipolar disorders. We employed quantitative immunocytochemistry to measure levels of Reelin protein in various compartments of hippocampal formation in subjects diagnosed with schizophrenia, bipolar disorder and major depression compared to normal controls. Significant reductions were observed in Reelin-positive adjusted cell densities in the dentate molecular layer (ANOVA, P < 0.001), CA4 area (ANOVA, P < 0.001), total hippocampal area (ANOVA, P < 0.038) and in Reelin-positive cell counts in CA4 (ANOVA, P < 0.042) of schizophrenics vs controls. Adjusted Reelin-positive cell densities were also reduced in CA4 areas of subjects with bipolar disorder (ANOVA, P < 0.001) and nonsignificantly in those with major depression. CA4 areas were also significantly reduced in schizophrenic (ANOVA, P < 0.009) patients. No significant effects of confounding variables were found. The exception was that family history of psychiatric illness correlated strongly with Reelin reductions in several areas of hippocampus (CA4, adjusted cell density, F = 13.77, P = 0.001). We present new immunocytochemical evidence showing reductions in Reelin expression in hippocampus of subjects with schizophrenia, bipolar disorder and major depression and confirm recent reports documenting a similar deficit involving Reelin expression in brains of subjects with schizophrenia and bipolar disorder.
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Two apolipoprotein E (apoE) receptors, the very low density lipoprotein (VLDL) receptor and apoE receptor 2 (apoER2), are also receptors for Reelin, a signaling protein that regulates neuronal migration during brain development. In the adult brain, Reelin is expressed by GABA-ergic interneurons, suggesting a potential function as a modulator of neurotransmission. ApoE receptors have been indirectly implicated in memory and neurodegenerative disorders because their ligand, apoE, is genetically associated with Alzheimer disease. We have used knockout mice to investigate the role of Reelin and its receptors in cognition and synaptic plasticity. Mice lacking either the VLDL receptor or the apoER2 show contextual fear conditioning deficits. VLDL receptor-deficient mice also have a moderate defect in long term potentiation (LTP), and apoER2 knockouts have a pronounced one. The perfusion of mouse hippocampal slices with Reelin has no effect on baseline synaptic transmission but significantly enhances LTP in area CA1. This Reelin-dependent augmentation of LTP is abolished in VLDL receptor and apoER2 knockout mice. Our results reveal a role for Reelin in controlling synaptic plasticity in the adult brain and suggest that both of its receptors are necessary for Reelin-dependent enhancement of synaptic transmission in the hippocampus. Thus, the impairment of apoE receptor-dependent neuromodulation may contribute to cognitive impairment and synaptic loss in Alzheimer disease.
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Autism is a complex neurodevelopmental disorder with severe cognitive and communication disabilities, that has a strong genetic predisposition. Reelin, a protein involved in neuronal migration during development, is encoded by a gene located on 7q22, within the candidate region on 7q showing increased allele sharing in previous genome scans. A case/control and family-based association study recently reported a positive association between a trinucleotide repeat polymorphism (GGC) located in the 5' untranslated region (UTR) of the reelin gene and autism. We performed a transmission disequilibrium test (TDT) analysis of the 5'UTR polymorphism in 167 families including 218 affected subjects (117 trios and 50 affected sib pairs) and found no evidence of linkage/association. Our results do not support previous findings and suggest that this GGC polymorphism of the reelin gene is unlikely to be a major susceptibility factor in autism and/or genetic heterogeneity.
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Between 1997 and 2002, 48 data sets from the hippocampus were produced on samples from the Stanley Neuropathology Consortium. From these data sets, 224 total measures were available from the various subdivisions of the hippocampus. An integrative analysis of these measures was performed using a multivariate, nonparametric analysis of variance (ANOVA). ANOVA with correction for multiple comparisons indicated that parvalbumin-containing cells in CA2 were reduced in schizophrenia and bipolar disorder. In addition, reelin protein in the molecular layer of the dentate gyrus was decreased in schizophrenia, bipolar disorder, and depression at the trend level of statistical significance (P=0.065). These results strongly suggest a dysfunction of inhibitory GABA-ergic interneurons in severe mental illness. Without correction for multiple comparisons, 31 measures were abnormal in at least one disease, whereas 11 measures would be expected to appear abnormal by chance. Abnormal molecules included measures of synaptic density or neuronal plasticity (reelin, SNAP-25, BDNF, Complexin I and II), as well as parvalbumin, tyrosine receptor kinase A, glucocorticoid receptors, glutamate NR1 receptor subunits, serotonin 5HT2(A) and 5HT1(B) receptors, and dopamine D(5) receptors.
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This the Diagnostic Interview for Genetic Studies (DIGS), a clinical interview especially constructed for the assessment of major mood and psychotic disorders and their spectrum conditions. The DIGS, which was developed and piloted as a collaborative effort of investigators from sites in the National Institute of Mental Health (NIMH) Genetics Initiative, has the following additional features: (1) polydiagnostic capacity; (2) a detailed assessment of the course of the illness, chronology of psychotic and mood syndromes, and comorbidity; (3) additional phenomenologic assessments of symptoms; and (4) algorithmic scoring capability. The DIGS is designed to be employed by interviewers who exercise significant clinical judgment and who summarize information in narrative form as well as in ratings. A two-phase test-retest (within-site, between-site) reliability study was carried out for DSM-III-R criteria—based major depression, bipolar disorder, schizophrenia, and schizoaffective disorder. Reliabilities using algorithms were excellent (0.73 to 0.95), except for schizoaffective disorder, for which disagreement on estimates of duration of mood syndromes relative to psychosis reduced reliability. A final best-estimate process using medical records and information from relatives as well as algorithmic diagnoses is expected to be more reliable in making these distinctions. The DIGS should be useful as part of archival data gathering for genetic studies of major affective disorders, schizophrenia, and related conditions.
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In studies conducted on largely treatment naive patients in their first episode of psychosis, we have found that treatment outcome is quite good and that most patients recover or at least achieve a substantial degree of symptom remission. However, over the course of their illness and in the context of subsequent psychotic episodes, they may experience some decrease in their treatment response from illness progression. In addition, the heterogeneity of treatment outcome is associated with specific clinical (gender, primary negative symptoms of the deficit state, duration of psychosis) and biological variables (pHVA, ventricular volume). It is unclear whether these variables represent aspects of discrete subtypes of schizophrenia or dimensional measures of pathology within the broad context of a unitary disease entity.
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The variable results of positive-negative research with schizophrenics underscore the importance of well-characterized, standardized measurement techniques. We report on the development and initial standardization of the Positive and Negative Syndrome Scale (PANSS) for typological and dimensional assessment. Based on two established psychiatric rating systems, the 30-item PANSS was conceived as an operationalized, drug-sensitive instrument that provides balanced representation of positive and negative symptoms and gauges their relationship to one another and to global psychopathology. It thus constitutes four scales measuring positive and negative syndromes, their differential, and general severity of illness. Study of 101 schizophrenics found the four scales to be normally distributed and supported their reliability and stability. Positive and negative scores were inversely correlated once their common association with general psychopathology was extracted, suggesting that they represent mutually exclusive constructs. Review of five studies involving the PANSS provided evidence of its criterion-related validity with antecedent, genealogical, and concurrent measures, its predictive validity, its drug sensitivity, and its utility for both typological and dimensional assessment.
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In an association analysis comparing cases and controls with respect to allele frequencies at a highly polymorphic locus, a potential problem is that the conventional chi-squared test may not be valid for a large, sparse contingency table. However, reliance on statistics with known asymptotic distribution is now unnecessary, as Monte Carlo simulations can be performed to estimate the significance level of any test statistic. We have implemented a Monte Carlo method for four 'chi-squared' test statistics, three of which involved combination of alleles, and evaluated their performance on a real data set. Combining rare alleles to avoid small expected cell counts, and considering each allele in turn against the rest, reduced the power to detect a genuine association when the number of alleles was very large. We should either not combine alleles at all, or combine them in such a way that preserves the evidence for an association.
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Many people with severe schizophrenia have increased cerebral ventricular size and diffuse reduction in cortical volume; recent attention has focused on subtle malformations of the cytoarchitecture in the hippocampus and parahippocampal cortex. Sufferers also show an excess of dermatoglyphic and minor physical abnormalities, and a significant proportion had psychomotor deficits, cognitive or behavioural problems as children. Such findings suggest that the form of schizophrenia most akin to Kraepelin's original description of dementia praecox results from neurodevelopmental impairment. This may have its origin in genetic defects in the control of early brain growth, or in early environmental hazards such as prenatal exposure to maternal influenza or perinatal complications. How foetal or neonatal lesions produce hallucinations and delusions two or three decades later remains a mystery, but maturational changes in the brain may be important.
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This article reports on the development and reliability of the Diagnostic Interview for Genetic Studies (DIGS), a clinical interview especially constructed for the assessment of major mood and psychotic disorders and their spectrum conditions. The DIGS, which was developed and piloted as a collaborative effort of investigators from sites in the National Institute of Mental Health (NIMH) Genetics Initiative, has the following additional features: (1) polydiagnostic capacity; (2) a detailed assessment of the course of the illness, chronology of psychotic and mood syndromes, and comorbidity; (3) additional phenomenologic assessments of symptoms; and (4) algorithmic scoring capability. The DIGS is designed to be employed by interviewers who exercise significant clinical judgment and who summarize information in narrative form as well as in ratings. A two-phase test-retest (within-site, between-site) reliability study was carried out for DSM-III-R criteria-based major depression, bipolar disorder, schizophrenia, and schizoaffective disorder. Reliabilities using algorithms were excellent (0.73 to 0.95), except for schizoaffective disorder, for which disagreement on estimates of duration of mood syndromes relative to psychosis reduced reliability. A final best-estimate process using medical records and information from relatives as well as algorithmic diagnoses is expected to be more reliable in making these distinctions. The DIGS should be useful as part of archival data gathering for genetic studies of major affective disorders, schizophrenia, and related conditions.
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The study attempted to identify pretreatment characteristics of chronic schizophrenic patients that would predict remission in psychosis and amount of clinical improvement after treatment with haloperidol. Thirty-five acutely relapsed schizophrenic patients were entered into a blind 6-week treatment protocol. Pretreatment measures were assessed for prediction of both remission status (dichotomous) and for correlations with change in psychopathology (continuous). Later age of onset and higher plasma homovanillic acid values were significant predictors of remission status (model 1). However, higher cerebrospinal fluid levels of 3-methoxy-4-hydroxyphenylglycol, as well as indices of normal neurodevelopment, predicted larger changes in psychopathology. The results indicate that the definition of drug response determines the predictive variables. Dopaminergic activity seems to relate to the ability to reach remission, while noradrenergic activity relates to symptom intensity and reduction. In addition to catecholamine activity, neurodevelopmental changes determine response to haloperidol.
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Reeler is an autosomal recessive mutation in mice that results in widespread disruption of laminated regions of the brain. We isolated a gene, reelin, that is mutated in reeler mice. The protein product of reelin has features of extracellular matrix components and it is expressed in a temporal and spatial pattern during embryonic and postnatal development consistent with the phenotypic defects in reeler mice. To understand the molecular basis of the function of Reelin, we constructed a full length reelin clone and used it to direct Reelin expression. Using this clone we found that Reelin is a secreted glycoprotein and that a highly charged C-terminal region is essential for secretion. Furthermore, we demonstrated that an amino acid sequence present in the N-terminal region of Reelin contains an epitope that is recognized by the CR-50 monoclonal antibody. CR-50 was raised against an antigen expressed in normal mouse brain that is absent in reeler mice. The interaction of CR-50 with its epitope has been shown to disrupt neuronal migration in vitro and in vivo. We used CR-50 to precipitate p385 Reelin from reticulocyte extracts programmed with reelin mRNA, from cells transfected with reelin clones and from cerebellar explants. Reelin appears to function as an instructive signal in the regulation of cell patterning during development.
Article
Cajal-Retzius (CR) cells of the cerebral cortex express receptors for the neurotrophin brain-derived neurotrophic factor (BDNF) and downregulate expression of the extracellular matrix protein Reelin during early postnatal development, coincident with the onset of cortical BDNF expression. During this period, mice lacking BDNF have elevated levels of Reelin in CR cells. Acute BDNF stimulation of cortical neuron cultures and overexpression of BDNF in the developing brain of transgenic mice prior to the onset of endogenous production causes a profound, dose-dependent reduction of Reelin expression in CR cells. In addition, overexpression of BDNF produces gaps and heterotopias in the marginal zone and disorganization and aggregation of cortical CR cells and induces several other malformations, including aberrant cortical lamination, similar to the phenotype of reeler mutant mice, which lack Reelin. These results demonstrate a role for BDNF on cortical CR cells and identify Reelin as a direct effector of this neurotrophin during brain development.
Article
Spielman and Ewens recently proposed a method for testing a marker for linkage with a disease, which combines data from families with and without information on parental genotypes. For some families without parental-genotype information, it may be possible to reconstruct missing parental genotypes from the genotypes of their offspring. The treatment of such a reconstructed family as if parental genotypes have been typed, however, can introduce bias. In the present study, a new method is presented that employs parental-genotype reconstruction and corrects for the biases resulting from reconstruction. The results of an application of this method to a real data set and of a simulation study suggest that this approach may increase the power to detect linkage.
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Schizophrenia is a psychiatric disorder that aCicts 0.5‐1% of the general population. It is clinically characterized by disturbed thought processes, delusions, hallucinations and/or reduced social skills (Andreasen, 1995). This severe mental disorder strikes human beings in their early adulthood, causes lifelong disability for most of the suAerers and is therefore one of the ten most expensive disorders worldwide. Its direct and indirect costs mount up to 33 billion dollars per year, while aCicting all ethic backgrounds, genders, socioeconomic classes and nationalities. The course of the illness is characterized by episodes of acute psychotic symptoms followed by phases of remission where symptoms like reduced drive and aAect as well as disturbed cognitive functions prevail. Despite the severeness of the disorder its origins are unclear until now. The neuropathological and neuroanatomical findings in patients with schizophrenia have been proposed to arise from dysfunction of structural reorganization during early brain development (Waddington, 1993; Weinberger, 1995), or postnatally from altered maturation of synaptic elimination (Feinberg, 1982). Morphometric and in vivo neuroimaging studies described enlarged ventricles, cerebral atrophy of temporal lobe and prefrontal structures, and increase in the gyrification index (Arnold and Trojanowski, 1996). One of the most consistent results is the lack of astrogliosis in schizophrenic brains, which would be a requirement for severe and chronic neurodegenerative
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The antipsychotics haloperidol and risperidone are widely used in the therapy of schizophrenia. The former drug mainly acts on the dopamine (DA) D(2) receptor whereas risperidone binds to both DA and serotonin (5HT) receptors, particularly in the neurons of striatal and limbic structures. Recent evidence suggests that neurotrophins might also be involved in antipsychotic action in the central nervous system (CNS). We have previously reported that haloperidol and risperidone significantly affect brain nerve growth factor (NGF) level suggesting that these drugs influence the turnover of endogenous growth factors. Brain-derived neurotrophic factor (BDNF) supports survival and differentiation of developing and mature brain DA neurons. We hypothesized that treatments with haloperidol or risperidone will affect synthesis/release of brain BDNF and tested this hypothesis by measuring BDNF and TrkB in rat brain regions after a 29-day-treatment with haloperidol or risperidone added to chow. Drug treatments had no effects on weight of brain regions. Chronic administration of these drugs, however, altered BDNF synthesis or release and expression of TrkB-immunoreactivity within the brain. Both haloperidol and risperidone significantly decreased BDNF concentrations in frontal cortex, occipital cortex and hippocampus and decreased or increased TrkB receptors in selected brain structures. Because BDNF can act on a variety of CNS neurons, it is reasonable to hypothesize that alteration of brain level of this neurotrophin could constitute one of the mechanisms of action of antipsychotic drugs. These observations also support the possibility that neurotrophic factors play a role in altered brain function in schizophrenic disorders.
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Antipsychotic response after the initiation of neuroleptic treatment shows wide variation in schizophrenic patient populations. In this overview, the authors suggest that the variance in antipsychotic drug response within schizophrenia can be reduced by resolving the schizophrenias into several discrete "endophenotypes," each with different etiologic underpinnings. Studies relating differences in the relative speed or completeness of antipsychotic response to differences in distribution of 2 biological markers with possible etiologic significance are reviewed. Such studies had assessed recently hospitalized, neuroleptic-free patients undergoing exacerbation of nonaffective psychotic disorders. Prior to initiation of neuroleptic, the cohort of patients had been assessed for the quantity of the dopamine metabolite homovanillic acid in plasma (pHVA) and had undergone the first of 2 magnetic resonance imaging (MRI) studies for analyses of ventricle volumes. A second MRI was subsequently performed during a period of (partial) remission to determine within-patient stability of ventricular volumes. These selected studies assessed the distribution of pHVA and distribution of rates of ventricular change, with non-normal distributions resolved by K-means clustering. The speed and completeness of neuroleptic-induced antipsychotic response were related to 3 clusters of patients delineated by modal distributions of pHVA and of apparent rates of ventricular change. At least 3 unique "endophenotypes" of the "group of the schizophrenias" can be defined with respect to speed and completeness of antipsychotic response. Each endophenotype appears to show at least one unique biological feature that differentiates it from a normal comparison group. A rapidly responsive psychosis was associated with excessive production of dopamine, as identifiable by elevation of pHVA and a "good-prognosis" course. A delayed-response psychosis had low-to-normal pHVA, clinically demonstrated persistent negative symptoms, and was associated with an excessive rate of change in ventricle volume between exacerbations of psychosis and (partial) remissions. Finally, a nonresponsive psychosis could be characterized as having both low-to-normal pHVA and rate of change of ventricle volumes similar to that of controls. Additional studies revealed that each of the endophenotypes had high rates of the psychoses in family members. The good-prognosis course of the rapidly responsive group of studied patients was also found in their family members who had psychotic disorders. Similarly, the prominent negative symptoms of the delayed-response probands were reflected as a prominent trait in their family members also afflicted with psychosis. The endophenotypes tended to "breed true" in terms of prognosis and negative symptoms. Major differences in antipsychotic response patterns appear to be associated with patient and family characteristics that may be related to differences in the etiology and consequent pathophysiology of illness.
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Autistic disorder (MIM 209850) is currently viewed as a neurodevelopmental disease. Reelin plays a pivotal role in the development of laminar structures including the cerebral cortex, hippocampus, cerebellum and of several brainstem nuclei. Neuroanatomical evidence is consistent with Reelin involvement in autistic disorder. In this study, we describe several polymorphisms identified using RNA-SSCP and DNA sequencing. Association and linkage were assessed comparing 95 Italian patients to 186 ethnically-matched controls, and using the transmission/disequilibrium test and haplotype-based haplotype relative risk in 172 complete trios from 165 families collected in Italy and in the USA. Both case-control and family-based analyses yield a significant association between autistic disorder and a polymorphic GGC repeat located immediately 5' of the reelin gene (RELN) ATG initiator codon, as well as with specific haplotypes formed by this polymorphism with two single-base substitutions located in a splice junction in exon 6 and within exon 50. Triplet repeats located in 5' untranslated regions (5'UTRs) are indicative of strong transcriptional regulation. Our findings suggest that longer triplet repeats in the 5'UTR of the RELN gene confer vulnerability to autistic disorder.
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In this review, we will first present a brief overview of the current understanding of: (a) the biology of reelin; (b) the putative reelin signaling pathways via integrin receptor stimulation; (c) the cytosolic adapter protein DAB1, which appears to be operative in the transduction of reelin's pleiotropic actions in embryonic, adolescent, and adult brain; (d) the regulation of GABAergic function, including some aspects of GABAergic system development; and (e) dendritic spine function and its role in the regulation of synaptic plasticity. We argue that a downregulation of reelin expression occurring in prefrontal cortex and in every brain structure of schizophrenia patients so far studied may be associated with a decrease in dendritic spine expression that in turn may provide an important reduction of cortical function as documented by the downregulation of glutamic acid decarboxylase67 (GAD67) expression, which might be secondary to a reduction of GABAergic axon terminals. This hypothesis is supported by a genetic mouse model of reelin haploinsufficiency that replicates the above-described dendritic and presynaptic GABAergic defects documented in schizophrenia brains.
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Proliferation and maturation of neurons has been demonstrated to occur at a significant rate in discrete regions of adult brain, including the hippocampus and subventricular zone. Moreover, adult neurogenesis is an extremely dynamic process that is regulated in both a positive and negative manner by neuronal activity and environmental factors. It has been suggested to play a role in several important neuronal functions, including learning, memory, and response to novelty. In addition, exposure to psychotropic drugs or stress regulates the rate of neurogenesis in adult brain, suggesting a possible role for neurogenesis in the pathophysiology and treatment of neurobiological illnesses such as depression, post-traumatic stress disorder, and drug abuse. As the mechanisms that control adult neurogenesis continue to be identified, the exciting prospect of developing pharmacological agents that specifically regulate the proliferation and maturation of neurons in the adult brain could be fulfilled.
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Reelin is a secreted extracellular matrix protein approximately 410 kDa mol. wt that is reduced in brains of patients with schizophrenia, autism, bipolar disorder and major depression. Recent reports also indicate its near absence in sera of some patients with an autosomal recessive form of lissencephaly. Moreover, Reelin is involved not only in normal cortical lamination of the brain during mammalian embryogenesis but is also implicated in cell signaling systems subserving cognition in adult brain. Here, we show that blood levels of Reelin and its isoforms are altered in three psychiatric disorders, namely, schizophrenia, bipolar disorder and major depression. The changes include significant increases in 410 kDa Reelin moiety of 49% in schizophrenic patients (p < 0.022) of four ethnic compositions (Caucasian, Vietnamese, Hmong and Laotian) and non-significant increases in depressed patients by 34% vs control blood. In contrast, 410 kDa Reelin levels decreased by 33% in bipolar blood, albeit non-signficantly, vs. controls. There was a significant increase of 90% (p < 0.0061) in 330 kDa Reelin in Caucasian schizophrenics; the depressed value was elevated by 30% vs. control but non-significantly. Again, in contrast, bipolar 330 kDa value decreased by 31% vs control (p < 0.0480). Finally, all 180 kDa Reelin values varied minimally in schizophrenics vs controls. In contrast, the 180 kDa Reelin values dropped significantly by 49% (p < 0.0117) and 29% (p < 0.0424) in bipolar and depressed patients, respectively, compared with controls. The alterations in blood Reelin values appear to be specific since levels of two other blood proteins, ceruloplasmin and albumin did not vary significantly between all psychiatric subjects and controls. These findings suggest that blood Reelin levels and its isoforms may be used as potential peripheral markers to diagnose presence of several psychiatric disorders and may also serve as targets for future therapeutic interventions.
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Based on a number of neuroanatomical and behavioural similarities, recent evidence suggests that heterozygous reeler mice, haploinsufficient for reelin expression, represent a useful model of psychosis vulnerability. As brain mesolimbic dopamine pathways have been proposed to be associated with the pathophysiology of psychotic disorders, we thought it would be of interest to examine whether these animals present disturbances in the mesolimbic dopamine system. To this end we studied by immunocytochemical, in situ hybridization procedures and receptor autoradiography, several markers of the mesotelencephalic dopamine pathway in heterozygous reeler mice and controls. We report that heterozygous reeler mice exhibit a reduction in the number of tyrosine hydroxylase-immunoreactive cell bodies and tyrosine hydroxylase mRNA levels in the ventral tegmental area, as well as a reduction of tyrosine hydroxylase and dopamine transporter immunoreactivity in the dopamine terminal fields of the limbic striatum. In these areas we also observed a reduction of dopamine D2 receptor mRNA. Finally, a marked increase in D3 receptor mRNA levels was observed concomitant with a significant increase in D3 binding sites. On the contrary, the nigrostriatal pathway did not show any significant alteration in heterozygous reeler mice with regards to the dopaminergic markers examined in substantia nigra cell bodies and dorsal striatum dopamine terminal fields. These results suggest a specific link between reelin-related neuronal pathology and dopamine involvement in the pathophysiology of psychotic disorders.
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Several lines of evidence suggest a possible role for reelin in the pathogenesis of neurodevelopmental diseases, particularly schizophrenia. Genes encoding reelin and proteins involved in the signal pathway of reelin are thus candidate genes for schizophrenia. We examined the polymorphic CGG repeat in the 5'-untranslated region (UTR) of the reelin gene, which was recently found to be associated with autistic disorder, and the CGG repeat in the 5' UTR region of the very low density protein receptor (VLDLR) gene, which was reported to be associated with sporadic Alzheimer's disease, for allelic association with schizophrenia. The subjects consisted of 150 patients and 150 controls matched for sex, age and ethnicity (Japanese). We found no significant association of schizophrenia with the trinucleotide repeat polymorphism of the reelin or VLDLR genes, suggesting that these polymorphisms do not have a major role in the pathogenesis of the disease.
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Mood disorders have traditionally been conceptualized as neurochemical disorders, but there is now evidence from a variety of sources demonstrating regional reductions in central nervous system (CNS) volume, as well as reductions in the numbers and/or sizes of glia and neurons in discrete brain areas. Although the precise cellular mechanisms underlying these morphometric changes remain to be fully elucidated, the data suggests that mood disorders are associated with impairments of structural plasticity and cellular resilience. Recent preclinical and clinical studies have shown that signaling pathways involved in regulating cell survival and cell death are long-term targets for the actions of antidepressants and mood stabilizers. Antidepressants, lithium, and valproate indirectly regulate a number of factors involved in cell survival pathways, including CREB, BDNF, Bcl-2, and MAP kinases, and may thus bring about some of their delayed long term beneficial effects via underappreciated neurotrophic effects. The future development of treatments that more directly target molecules involved in critical CNS cell survival and cell death pathways thus hold promise as novel, improved long-term treatments for mood disorders.
Article
Two main pieces of neurobiological evidence are adduced to support an early neurodevelopmental component to schizophrenia. Firstly, an abnormal distribution of neurons, especially interstitial white matter neurons (IWMNs). Secondly, decreased expression of reelin, a key developmental signalling molecule. Although influential, neither result is wholly established, and a possible link between them has not been examined. We addressed both issues, in superior temporal cortex, in 12 subjects with schizophrenia and 14 controls. The distribution and density of IWMNs, immunostained with the neuronal marker NeuN, was increased in the superficial white matter in schizophrenia (+16%; P=0.03). IWMN density in deep white matter was unaffected. Using in situ hybridization, reelin mRNA was found to be expressed by many IWMNs, layer I neurons, and scattered interneurons. Superficial IWMNs (P=0.008) and layer I neurons (P=0.036) both expressed less reelin mRNA per cell in schizophrenia, with a trend for deep IWMNs (P=0.055). In conclusion, we replicated findings of increased IWMN density, and of decreased reelin expression, in schizophrenia. The loss of reelin reflects, at least partly, its decreased expression by IWMNs. These findings together support neurodevelopmental theories of the disorder, and indicate a link between reelin and IWMNs in this process, consistent with evidence from the heterozygous reeler mutant mouse. The alterations may contribute to the aberrant synaptic connectivity seen in schizophrenia. However, the functional implications of the abnormalities, as well as the mechanisms involved, remain to be fully elucidated.
Altered levels of Reelin and its isoforms in schizophrenia and mood disorders
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