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Pathogenicity of Antibodies against NMDA Receptor: Molecular Insights into Autoimmune Psychosis

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Abstract

Recent years have seen a flourishing literature on detection of circulating autoantibodies against neurotransmitter receptors in patients with neuropsychiatric disorders. These studies have generated hope for a better understanding of the underlying molecular dysfunctions and for appropriate therapeutic strategies. However, the detection of these autoantibodies in healthy subjects, and the lack of mechanistic insights have fostered debate about the pathogenic role of such autoantibodies. Here, we specifically discuss the biological evidence linking autoantibodies directed against the glutamatergic N-methyl-d-aspartate (NMDA) receptor (NMDAR-Abs) and psychosis, emphasising recent single-molecule imaging investigations that unveiled the impaired surface trafficking of NMDAR in the presence of NMDAR-Abs from psychotic patients. Although still in its infancy, the hypothesis that NMDAR-Abs from patients with psychosis play a pathogenic role is thus gaining support, opening avenues of fundamental and translational investigations.

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... The question of whether different clinical expression of anti-NMDAR encephalitis exists is a current debate. For instance, NMDAR-Abs have been found in up 20% of patients diagnosed with schizophrenia (Jezequel et al., 2018), suggesting that these autoantibodies can be expressed in patients with psychosis and/or in patients with anti-NMDAR encephalitis with prominent psychiatric features. Ongoing investigations will surely shed lights on this debate. ...
... The concept that autoantibodies contribute to the etiology of specific neurological and psychiatric conditions is almost a century old (Jezequel et al., 2018). Yet, since the identification of NMDAR-Abs in anti-NMDAR encephalitis more than a decade ago, the number of studies reporting NMDAR-autoimmunity in brain disorders has been exponentially growing (Dalmau et al., 2019;Ehrenreich, 2018;Jezequel et al., 2018). ...
... The concept that autoantibodies contribute to the etiology of specific neurological and psychiatric conditions is almost a century old (Jezequel et al., 2018). Yet, since the identification of NMDAR-Abs in anti-NMDAR encephalitis more than a decade ago, the number of studies reporting NMDAR-autoimmunity in brain disorders has been exponentially growing (Dalmau et al., 2019;Ehrenreich, 2018;Jezequel et al., 2018). The study of NMDAR-Abs has primarily focussed on neuropsychiatric diseases, since they were initially found in the serum and CSF of women presenting with prominent psychiatric symptoms and underlying ovarian teratoma (Dalmau et al., 2019). ...
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Over the past decades, the identification of autoimmune encephalitis in which patients express autoantibodies directed against neurotransmitter receptors has generated great hope to shed new light on the molecular mechanisms underpinning neurological and psychiatric conditions. Among these autoimmune encephalitides, the discovery of autoantibodies directed against the glutamatergic NMDA receptor (NMDAR-Ab), in the anti-NMDAR encephalitis, has provided some key information on how complex neuropsychiatric symptoms can be caused by a deficit in NMDAR signalling. Yet, NMDAR-Abs have also been detected in several neurological and psychiatric conditions, as well as in healthy individuals. In addition, these various NMDAR-Abs appear to have different molecular properties and pathogenicities onto receptors and synaptic functions. Here, we discuss the current view on the variety of NMDAR-Abs and, in particular, how these autoantibodies can lead to receptor dysfunction in neuronal networks. Since our mechanistic understanding on patients' NMDAR-Abs is still in its infancy, several complementary processes can be proposed and further in-depth molecular and cellular investigations will surely reveal key insights. Autoantibodies represent a great opportunity to gain knowledge on the etiology of neuropsychiatric disorders and pave the way for innovative therapeutic strategies. One sentence summary Current view on patients' autoantibody against NMDAR.
... Furthermore, clinical trials have reported significant improvements in cognitive function in patients with schizophrenia following D-serine treatment [21,22]. Psychosis is also a key symptom of anti-NMDAR encephalitis, and anti-NMDAR antibodies have been detected in a small group of patients with schizophrenia [23,24], suggesting potential similarities in the pathological changes between anti-NMDAR encephalitis and schizophrenia. Therefore, based on the theoretical foundation of NMDAR hypofunction induced by anti-NMDAR antibodies, it is reasonable to investigate whether the application of D-serine could improve NMDAR hypofunction in anti-NMDAR encephalitis and, consequently, enhance cognitive function. ...
... In patients with schizophrenia, decreased serum or CSF D-serine levels have been associated with cognitive impairment [38]. Considering the potential parallels between these conditions [23], it is worth investigating whether changes in D-serine levels have similar impacts in anti-NMDAR encephalitis. ...
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Objective: To establish a mouse model of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and assess the potential therapeutic benefits of D-serine supplementation in mitigating synaptic plasticity impairments induced by anti-NMDAR antibodies. Methods: Anti-NMDAR antibodies were purified from cerebrospinal fluid (CSF) samples of patients diagnosed with anti-NMDAR encephalitis and verified using a cell-based assay. CSF from patients with non-inflammatory neurological diseases served as the control. These antibodies were then injected intraventricularly into C57BL/6 mice. Forty-eight hours following the injection, mice were administered either D-serine (500 mg/kg) or sterile saline intraperitoneally for three consecutive days. Subsequent analyses included Western blotting, immunofluorescence, electrophysiological studies, and a series of behavioral tests to assess pathological changes caused by anti-NMDAR antibodies. Results: Mice injected with anti-NMDAR antibodies exhibited a significant reduction in hippocampal long-term potentiation compared to controls, which was notably ameliorated by D-serine treatment. Additionally, these mice displayed decreased levels of hippocampal membrane NMDAR1 protein and postsynaptic NMDAR1 density. However, D-serine administration did not significantly alter these conditions. Notably, no significant behavioral differences were observed between mice injected with anti-NMDAR antibodies and controls in open fields, elevated plus maze, novel object recognition, or Morris water maze tests. Conclusions: Our findings indicate that exogenous D-serine can improve hippocampal plasticity impairments caused by anti-NMDAR antibodies but does not reverse the decreased expression of NMDAR. Furthermore, a single intraventricular injection of patients’ antibodies was insufficient to induce anti-NMDAR encephalitis-related behaviors in mice.
... A meta-analysis study of seven reports also demonstrated that anti-NMDAR antibodies were detected in 8% of patients with schizophrenia (115/1441) [58]. Furthermore, a recent OPTIMISE project also reported that approximately 5% of firstepisode psychosis patients without antipsychotic exposure were positive for anti-NMDAR antibodies [59]. Notably, the serum levels of anti-NMDAR antibodies in first-episode patients with schizophrenia were positively correlated with the severity of schizophrenia using PANS scores [60]. ...
... NMDAR antagonists directly inhibit the permeability of channel pores, whereas NMDAR antibodies have no direct effect on channel-pore function [62]. However, anti-NMDAR antibodies lead to the internalization/downregulation of NMDARs [59,[63][64][65]. These preclinical findings suggest that decreasing NMDAR activity by either decreasing functional NMDARs in the plasma membrane or directly inhibiting channels plays an important role in the negative symptoms and cognitive impairments caused by schizophrenia. ...
Article
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For several decades, the dopamine hypothesis contributed to the discovery of numerous typical and atypical antipsychotics and was the sole hypothesis for the pathophysiology of schizophrenia. However, neither typical nor atypical antipsychotics, other than clozapine, have been effective in addressing negative symptoms and cognitive impairments, which are indices for the prognostic and disability outcomes of schizophrenia. Following the development of atypical antipsychotics, the therapeutic targets for antipsychotics expanded beyond the blockade of dopamine D2 and serotonin 5-HT2A receptors to explore the partial agonism of the D2 receptor and the modulation of new targets, such as D3, 5-HT1A, 5-HT7, and metabotropic glutamate receptors. Despite these efforts, to date, psychiatry has not successfully developed antipsychotics with antipsychotic properties proven to be superior to those of clozapine. The glutamate hypothesis, another hypothesis regarding the pathophysiology/pathomechanism of schizophrenia, was proposed based on clinical findings that N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists, such as phencyclidine and ketamine, induce schizophrenia-like psychotic episodes. Large-scale genome-wide association studies (GWASs) revealed that approximately 30% of the risk genes for schizophrenia (the total number was over one hundred) encode proteins associated with glutamatergic transmission. These findings supported the validation of the glutamate hypothesis, which was inspired by the clinical findings regarding NMDAR antagonists. Additionally, these clinical and genetic findings suggest that schizophrenia is possibly a syndrome with complicated pathomechanisms that are affected by multiple biological and genetic vulnerabilities. The glutamate hypothesis has been the most extensively investigated pathophysiology/pathomechanism hypothesis, other than the dopamine hypothesis. Studies have revealed the possibility that functional abnormalities of the NMDAR play important roles in the pathophysiology/pathomechanism of schizophrenia. However, no antipsychotics derived from the glutamatergic hypothesis have yet been approved for the treatment of schizophrenia or treatment-resistant schizophrenia. Considering the increasing evidence supporting the potential pro-cognitive effects of glutamatergic agents and the lack of sufficient medications to treat the cognitive impairments associated with schizophrenia, these previous setbacks cannot preclude research into potential novel glutamate modulators. Given this background, to emphasize the importance of the dysfunction of the NMDAR in the pathomechanism and/or pathophysiology of schizophrenia, this review introduces the increasing findings on the functional abnormalities in glutamatergic transmission associated with the NMDAR.
... 11 Previous studies demonstrated that NMDAR surface dynamics are impaired by NMDAR-Ab from patients with NMDARe. 2,12,13 In the presence of NMDAR-Ab, the nanoscale organization and dynamics of NMDAR are disrupted, contributing to the deficit in NMDAR-mediated synaptic transmission and plasticity. 2,3,[12][13][14] Identifying ways to directly act on NMDAR nanoscale organization and dynamics would thus represent a novel treatment strategy for this disorder. ...
... 2,12,13 In the presence of NMDAR-Ab, the nanoscale organization and dynamics of NMDAR are disrupted, contributing to the deficit in NMDAR-mediated synaptic transmission and plasticity. 2,3,[12][13][14] Identifying ways to directly act on NMDAR nanoscale organization and dynamics would thus represent a novel treatment strategy for this disorder. ...
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Objectives A positive allosteric modulator of the NMDAR, SGE-301, has been shown to reverse the alterations caused by the antibodies of patients with anti-NMDAR encephalitis (NMDARe). However, the mechanisms involved beyond receptor modulation are unclear. In this study, we aimed to investigate how this modulator affects NMDAR membrane dynamics. Methods Cultured hippocampal neurons were treated with SGE-301 or vehicle, alongside with immunoglobulins G (IgG) from patients with NMDARe or healthy controls. NMDAR surface dynamics were assessed with single-molecule imaging by photoactivated localization microscopy. Results NMDAR trajectories from neurons treated with SGE-301 were less confinement, with increased diffusion coefficients. This effect mainly occurred at synapses because extrasynaptic diffusion and confinement were minimally affected by SGE-301. Treatment with patients' IgG reduced NMDAR surface dynamics and increased their confinement. Remarkably, SGE-301 incubation antagonized patients' IgG effects in both synaptic and extrasynaptic membrane compartments, restoring diffusion and confinement values similar to those from neurons exposed to control IgG. Discussion We demonstrate that SGE-301 upregulates NMDAR surface diffusion and antagonizes the pathogenic effects of patients' IgG on NMDAR membrane organization. These findings suggest a potential therapeutic strategy for NMDARe.
... Accumulating evidence suggests that the nature of antibodymediated NMDAR hypofunction is the internalization of NMDARs, through the process of antibody-mediated cross-linking followed by a reduction of NMDAR clusters from the neuronal surface (Hughes et al., 2010;Jezequel, Johansson, Leboyer, & Groc, 2018;Mikasova et al., 2012;Moscato et al., 2014). Recently, superresolution microscopy in cultured hippocampal pyramidal neurons was used to visualize the clustering and internalization of synaptic receptors with antibody stimulation. ...
... In another meta-analysis study of seven reports comprising 1441 patients with idiopathic schizophrenia, 115 (8%) of patients were seropositive for anti-NMDAR antibodies (Pollak et al., 2014). From the recent OPTIMISE project, approximately 5% of NMDAR autoantibody seropositive patients were identified among first-episode psychosis patients with minimal or no exposure to antipsychotics (Jezequel et al., 2018). Another single large study emphasized that NMDAR antibodies are significantly more prevalent in patients with first-episode psychosis patients (seven [3%] of 228 participants) than in controls (0 of 105 participants) (Lennox et al., 2017). ...
Article
N-methyl-D-aspartate (NMDA) receptor (NMDAR) hypofunction plays a key role in pathophysiology of schizophrenia. Since NMDAR hypofunction has also been reported in autism, Alzheimer's disease and cognitive dementia, it is crucial to identify the location, timing, and mechanism of NMDAR hypofunction for schizophrenia for better understanding of disease etiology and for novel therapeutic intervention. In this review, we first discuss the shared underlying mechanisms of NMDAR hypofunction in NMDAR antagonist models and the anti-NMDAR autoantibody model of schizophrenia and suggest that NMDAR hypofunction could occur in GABAergic neurons in both models. Preclinical models using transgenic mice have shown that NMDAR hypofunction in cortical GABAergic neurons, in particular parvalbumin-positive fast-spiking interneurons, in the early postnatal period confers schizophrenia-related phenotypes. Recent studies suggest that NMDAR hypofunction can also occur in PV-positive GABAergic neurons with alterations of NMDAR-associated proteins, such as neuregulin/ErbB4, α7nAChR, and serine racemase. Furthermore, several environmental factors, such as oxidative stress, kynurenic acid and hypoxia, may also potentially elicit NMDAR hypofunction in GABAergic neurons in early postnatal period. Altogether, the studies discussed here support a central role for GABAergic abnormalities in the context of NMDAR hypofunction. We conclude by suggesting potential therapeutic strategies to improve the function of fast-spiking neurons.
... В последнее время увеличилось число опубликованных в литературе данных, свидетельствующих в пользу причинной роли аутоантител при первичных психических заболеваниях [59]. Однако обнаружение у здоровых и недостаточное понимание механизмов действия таких антител способствуют продолжению дискуссии об их роли в развитии ШЗ, тем более отмечаются очевидные различия в методических подходах к их определению в разных исследованиях. ...
... Большое место в литературе занимает обсуждение вопроса о действии аутоантител на механизмы нейровоспаления и возможности терапии влиять на эти процессы [59,60]. В связи с этим следует отметить, что вероятность развития некоторых аутоиммунных заболеваний, в частности ревматоидного артрита, при ШЗ снижена. ...
Article
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The review addresses immunological aspects of schizophrenia, a multifactor disease caused by genetic factors, innate disorders of the central nervous system (CNS), including the consequences of perinatal hypoxia and infections, and adverse environmental influences. Neuroinflammation as a part of the pathophysiology of schizophrenia is characterized by the higher transcription of CNS inflammatory mediators, excessive activation of microglia, inhibition of glutamatergic receptors that leads to the decrease in the number of cortical synapses and neuronal apoptosis. The authors discuss a role of genetic polymorphisms of cytokine genes, complement system components etc. The literature data on the changes in systemic immune response and imbalance in Th1/Th2 adaptive immune responses are analyzed as well. Some papers showed higher levels of proinflammatory mediators in CSF and blood of patients with schizophrenia that indicated the involvement of blood brain barrier (BBB) dysfunction. The authors present the recent data on BBB dysfunction in schizophrenia and its role in the pathogenesis of the disease, autoimmunity in patients comparing it with immune activation and genetic predisposition. An important and arguable issues about a role of parasite and viral infections in the pathogenesis of schizophrenia, initiation of immune responses and direct impacts on the brain, an influence of antipsychotic treatment on immunity are discussed. In author's opinion, conflicting results of genetic and immunological studies of schizophrenia may be explained by different methodological approaches to selection of patients and healthy controls and the differences in schizophrenia classification.
... alone have been associated to the emergence of psychotic disorders 78 , and more broadly receptor hetero-complexes to understand their roles in health and major brain neuropsychiatric disorders [79][80][81][82][83][84] . ...
Article
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Direct interactions between receptors at the neuronal surface have long been proposed to tune signaling cascades and neuronal communication in health and disease. Yet, the lack of direct investigation methods to measure, in live neurons, the interaction between different membrane receptors at the single molecule level has raised unanswered questions on the biophysical properties and biological roles of such receptor interactome. Using a multidimensional spectral single molecule-localization microscopy (MS-SMLM) approach, we monitored the interaction between two membrane receptors, i.e. glutamatergic NMDA (NMDAR) and G protein-coupled dopamine D1 (D1R) receptors. The transient interaction was randomly observed along the dendritic tree of hippocampal neurons. It was higher early in development, promoting the formation of NMDAR-D1R complexes in an mGluR5- and CK1-dependent manner, favoring NMDAR clusters and synaptogenesis in a dopamine receptor signaling-independent manner. Preventing the interaction in the neonate, and not adult, brain alters in vivo spontaneous neuronal network activity pattern in male mice. Thus, a weak and transient interaction between NMDAR and D1R plays a structural and functional role in the developing brain.
... It is responsible for various neurological symptoms such as psychosis, seizures, abnormal behaviors, and cognitive manifestations (Lynch et al., 2018;Dalmau et al., 2019). NMDAR internalization causes NMDAR hypofunction in anti-NMDAR encephalitis, a process where antibodies crosslink NMDARs on the surface of neurons, resulting in a reversible reduction of NMDARs on the surface (Hughes et al., 2010;Mikasova et al., 2012;Moscato et al., 2014;Jézéquel et al., 2018). Molecular studies about the antibody binding sites identified that antibodies recognize the epitope on NTD of GluN1 in anti-NMDAR encephalitis, which contains N368/G369 (Dalmau et al., 2008;Gleichman et al., 2012;Kreye et al., 2016;Sharma et al., 2018;Jones et al., 2019). ...
Article
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N-methyl-D-aspartate receptors (NMDA) are glutamate-gated ion channels critical for synaptic transmission and plasticity. A slight variation of NMDAR expression and function can result in devastating consequences, and both hyperactivation and hypoactivation of NMDARs are detrimental to neural function. Compared to NMDAR hyperfunction, NMDAR hypofunction is widely implicated in many neurological disorders, such as intellectual disability, autism, schizophrenia, and age-related cognitive decline. Additionally, NMDAR hypofunction is associated with the progression and manifestation of these diseases. Here, we review the underlying mechanisms of NMDAR hypofunction in the progression of these neurological disorders and highlight that targeting NMDAR hypofunction is a promising therapeutic intervention in some neurological disorders.
... Nevertheless, it has to be kept in mind that it is very difficult to compare behavioral manifestations in animals with psychiatric and cognitive symptoms in humans. Thus, more research is needed to characterize the pathogenic role of NMDAR autoantibodies in humans [33] such as a role in generating psychotic symptoms [34,35]. ...
Article
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N-Methyl-d-Aspartate-receptor (NMDAR) antibody encephalitis is a disease discovered two decades ago. Our knowledge about it has recently deepened dramatically. However, the significance of NMDAR antibodies in psychiatric disease cannot be determined if there are no clear indications of brain inflammation or an autoimmune encephalitis mediated by NMDAR antibodies. Furthermore, the long-term interaction and connection between these two disease entities are unclear. In this paper we aim to elucidate the relationship between these disease entities. We propose two distinct models that explain the on the one hand a condition in which a minor inflammatory state as in psychiatric disease culminates in a severe state of inflammation characterized by NMDAR encephalitis. On the other hand, we postulate a model in which an NMDAR encephalitis might later create favorable conditions for inducing psychiatric disease. These models should be kept in mind for further investigations examining the long-term outcome of NMDAR autoantibody immunity in the brain and its functions.
... Fifth, due to the interval from symptom onset to antibody testing among some patients, it is plausible that a proportion of cases categorised as serum-only NMDAR-antibody positive may have been CSF positive at an earlier stage. Sixth, few studies reported the titre of autoantibodies detected, which has been shown to relate to pathogenic potential [16,17]. It is important to acknowledge that NMDARE with purely isolated psychiatric syndrome with CSF NMDAR autoantibodies is rare. ...
Article
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Background A variety of psychiatric syndromes are associated with NMDAR autoantibodies; however, their clinical relevance when only present in the serum is unclear. We explored whether patients with CSF NMDAR autoantibodies could be distinguished from patients with serum-only NMDAR autoantibodies. Methods The electronic databases MEDLINE, EMBASE, PubMed, and PsycINFO were searched. Articles reporting adult patients with isolated psychiatric features and positive for NMDAR autoantibodies with relevant investigations were included. Patient level meta-analysis compared patients positive for CSF NMDAR autoantibodies with patients positive for serum NMDAR autoantibodies, but negative for CSF NMDAR autoantibodies. Dichotomous data were analysed using crude odds ratios (OR), whilst continuous data were analysed using Mann–Whitney Test (U). The protocol was prospectively registered (CRD42018082210). Results Of 4413 publications, 42 were included, reporting 79 patients. Median age was 34 years (IQR 19 years); 56% (45/79) were female and 24% (16/68) had a tumour. In total, 41 patients were positive for CSF autoantibodies and 20 were positive for serum-only autoantibodies. Patients with CSF autoantibodies were significantly more likely to be female (p < 0.001) and have a rapid (< 3 month) onset of symptoms (p = 0.02) than patients with serum-only autoantibodies. They were also more likely to present with psychosis (p < 0.001), exhibit EEG (p = 0.006), MRI (p = 0.002), and CSF (p = 0.001) abnormalities, but less likely to present with insomnia (p = 0.04). Conclusions Patients with an isolated psychiatric syndrome with CSF NMDAR autoantibodies can potentially be distinguished from those with serum-only NMDAR autoantibodies based on clinicodemographic and investigation findings.
... Meanwhile, schizophrenia patients might have certain immunological aberrations that are related to the persistence of attenuated niacin-induced flush response. Increasing evidence indicates that there are immune system disturbances in schizophrenia 42,43 , e.g., autoantibodies to neurotransmitter receptors [44][45][46] or inflammation 47,48 . Whether these immune system disturbances are associated with the aberrations in niacin-induced flush response in schizophrenia warrants future investigation. ...
Article
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Despite the consistent finding of an attenuated niacin-induced flush response in schizophrenia, its long-term stability and relationship to the membrane polyunsaturated fatty acid (PUFA) levels remain unknown. We conducted niacin skin tests and measured the membrane PUFAs using gas chromatography among 46 schizophrenia inpatients and 37 healthy controls at the baseline and the 2-month follow-up. Attenuated flush responses were persistently observed in schizophrenia patients in both acute and partial remission states, whereas an increased flush response was found in the controls. A persistent decrease in both dihomo-gamma-linolenic acid and docosahexaenoic acid and an increased turnover of arachidonic acid (ARA) via endogenous biosynthesis were found in schizophrenia patients. A composite niacin flush score by combining those with a control-to-case ratio of >1.4 (i.e., scores at 5 min of 0.1 M, 0.01 M, and 0.001 M + 10 min of 0.01 M and 0.001 M + 15 min of 0.001 M) at the baseline was correlated positively with ARA levels among controls but not among schizophrenia patients, whereas the flush score at the 2-month follow-up was correlated positively with ARA levels among patients. The 2-month persistence of attenuated niacin-induced flush response in schizophrenia patients implies that the niacin skin test might tap a long-term vulnerability to schizophrenia beyond acute exacerbation.
... . Other neuropsychiatric disorders have often been associated with anti-NMDAR Abs detection, such as PD(Dahm et al., 2014), dementia(Busse et al., 2014), autism(Creten et al., 2011;Scott et al., 2014;Hacohen et al., 2016), bipolar disorder(Eaton et al., 2010;Dickerson et al., 2012;Sidhom et al., 2012;Hammer et al., 2014;Pearlman and Najjar, 2014), MDD(Pearlman and Najjar, 2014), and, most notably, the psychotic disorder schizophrenia(Ezeoke et al., 2013;Pearlman and Najjar, 2014;Pollak et al., 2014;Jézéquel et al., 2018;Tong et al., 2019). ...
Thesis
N-Methyl-D-Aspartate glutamate receptors (NMDAR) are key actors of excitatory synaptic transmission, synaptic plasticity and higher brain functions such as memory formation and learning. As a consequence, NMDAR dysfunctions are associated to pathological states and high investments have been made to develop modulators of NMDAR activity for clinical applications. While some NMDAR antagonists such as ketamine (anesthetic, antidepressant) or memantine (prescribed as a treatment for Alzheimer’s disease) have proven of great medical value, their clinical use is often limited by severe adverse effects (e.g. psychotic-like states induced by ketamine) and several questions regarding their action mode - including why some antagonists exhibit psychoactive properties when others do not - remain unanswered. Accumulating evidence suggests that beyond their channel function, physiological and pathological NMDAR signaling may involve non-canonical pathways independent from ion flux. Using a combination of epifluorescence, FRET-FLIM, biochemistry and single molecule localization microscopy approaches, we investigated the impact of competitive (D-AP5, CPP) and uncompetitive (MK-801, ketamine, memantine) NMDAR antagonists on the properties, redistribution and subsynaptic organization of surface NMDAR and their cytosolic partners in hippocampal neurons. We found that while all antagonists produce comparable inhibition of NMDAR ionotropic activity, exposure to the psychotomimetic blockers MK-801 and ketamine selectively triggers changes in the conformation of NMDAR. Interestingly, these conformational rearrangements were associated with a decreased surface diffusion and an increased residency time of receptors at synapses, suggesting MK-801 and ketamine binding possibly enhance NMDAR synaptic anchoring. Although drug exposure (1h) did not change the overall receptor abundance at excitatory synapses, super-resolution imaging revealed profound and antagonist-specific nanoscale reorganizations of synaptic NMDAR clusters, with exposure to the competitive antagonist D-AP5 causing a reduction in the size and an increase in the density of receptor nanodomains while inhibition by the uncompetitive psychotomimetic blockers MK-801 and ketamine triggered an enlargement of receptor nanodomains, and exposure to memantine prompted the fragmentation of these nanodomains. Moreover, we found that MK-801 and ketamine selectively enhanced the mobility of Ca2+/calmodulin-dependent protein kinase II (CaMKII) within dendritic spines through an action mode that relies on the direct interaction between both partners, suggesting that drug-induced receptor redistributions may impact the intracellular dynamics and organization of downstream signaling partners of NMDAR. Altogether, our results provide evidence that besides inhibition of ion fluxes through the receptors, competitive and uncompetitive antagonists have a different impact on NMDAR surface dynamics and subsynaptic organization, and suggest that the psychoactive blockers MK-801 and ketamine may act on receptor function through non-canonical rearrangements in the organization of NMDAR signaling complexes.
... Finally, we altered NMDAR surface diffusion by injecting GluN1 antibodies in a purely artificial manner. Yet, auto-antibodies against NMDARs were identified in the serum and the cerebrospinal fluid of patients suffering from a severe form of encephalitis (Dalmau et al. 2007) and psychotic disorders (Jézéquel et al. 2017(Jézéquel et al. , 2018. These auto-antibodies recognized an epitope localized in the extracellular part of the GluN1 subunit (Dalmau et al. 2007), profoundly altered NMDAR surface trafficking (Mikasova et al. 2012;Dupuis et al. 2014), and blocked the synaptic long-term potentiation (LTP) in hippocampal neurons Jéezéquel et al. 2017). ...
Article
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Key points NMDA receptors (NMDARs) expressed by dopamine neurons of the ventral tegmental area (VTA) play a central role in glutamate synapse plasticity, neuronal firing and adaptative behaviours. The NMDAR surface dynamics shapes synaptic adaptation in hippocampal networks, as well as associative memory. We investigated the basic properties and role of the NMDAR surface dynamics on cultured mesencephalic and VTA dopamine neurons in rodents. Using a combination of single molecule imaging and electrophysiological recordings, we demonstrate that NMDARs are highly diffusive at the surface of mesencephalic dopamine neurons. Unexpectedly, the NMDAR membrane dynamics per se regulates the firing pattern of VTA dopaminergic neurons, probably through a functional interplay between NMDARs receptors and small‐conductance calcium‐dependent potassium (SK) channels. Abstract Midbrain dopaminergic (DA) neurons play a central role in major physiological brain functions, and their dysfunctions have been associated with neuropsychiatric diseases. The activity of midbrain DA neurons is controlled by ion channels and neurotransmitter receptors, such as the glutamate NMDA receptor (NMDAR) and small‐conductance calcium‐dependent potassium (SK) channels. However, the cellular mechanisms through which these channels tune the firing pattern of midbrain DA neurons remain unclear. Here, we investigated whether the surface dynamics and distribution of NMDARs tunes the firing pattern of midbrain DA neurons. Using a combination of single molecule imaging and electrophysiological recordings, we report that NMDARs are highly diffusive at the surface of cultured midbrain DA neurons from rodents and humans. Reducing acutely the NMDAR membrane dynamics, which leaves the ionotropic function of the receptor intact, robustly altered the firing pattern of midbrain DA neurons without altering synaptic glutamatergic transmission. The reduction of NMDAR surface dynamics reduced apamin (SK channel blocker)‐induced firing change and the distribution of SK3 channels in DA neurons. Together, these data show that the surface dynamics of NMDAR, and not solely its ionotropic function, tune the firing pattern of midbrain DA neurons partly through a functional interplay with SK channel function.
... Intriguingly, the occurrence of IgG Aabs against neurotransmitter receptors and other macromolecules (DNA, brain lipids, gangliosides, and cardiolipin) has been described in a proportion of SCZ and BPD patients 13,14 . Particularly, IgG Aabs against neuronal receptors like N-methyl-Daspartate receptor (NMDAR), γ-aminobutyric acid receptor (GABAR), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) have been observed during the psychotic crisis 15,16 . Also, a systematic study by Pearlman and Najjar revealed a high prevalence of anti-NMDAR IgG Abs in SCZ patients and to a lesser extent in BPD patients 17 . ...
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It is not uncommon to observe autoimmune comorbidities in a significant subset of patients with psychotic disorders, namely schizophrenia (SCZ) and bipolar disorder (BPD). To understand the autoimmune basis, the DNA abyzme activity mediated by serum polyclonal IgG Abs were examined in psychoses patients, quantitatively, by an in-house optimized DNase assay. A similar activity exhibited by IgG Abs from neuropsychiatric-systemic lupus erythematosus (NP-SLE) patients was used as a comparator. Our data revealed that the IgG DNase activity of SCZ was close to that of NP-SLE and it was twofold higher than the healthy controls. Interestingly, the association between DNase activity with PANSS (positive, general and total scores) and MADRS were noted in a subgroup of SCZ and BPD patients, respectively. In our study group, the levels of IL-6 and total IgG in BPD patients were higher than SCZ and healthy controls, indicating a relatively inflammatory nature in BPD, while autoimmune comorbidity was mainly observed in SCZ patients.
... The mechanism of Ab-mediated NMDAR effect is the internalization and cross-linking of the receptor, resulting in a decrease in the availability of functional NMDAR. 27,28 Meta-analyses showed about 8% of patients with schizophrenia to be seropositive NMDAR Ab, which was 3 times higher than healthy subjects. 29 About 5% of patients with first-episode psychosis may already show seropositive NMDAR Ab. 30 One study showed 10.5% seropositive NMDAR Ab in both schizophrenia and healthy control (HC) subjects. ...
Article
Insufficient or lack of response to antipsychotic medications in some patients with schizophrenia is a major challenge in psychiatry, but the underlying mechanisms remain unclear. Two seemingly unrelated observations, cerebral white matter and N-methyl-D-aspartate receptor (NMDAR) hypofunction, have been linked to treatment-resistant schizophrenia (TRS). As NMDARs are critical to axonal myelination and signal transduction, we hypothesized that NMDAR antibody (Ab), when present in schizophrenia, may impair NMDAR functions and white matter microstructures, contributing to TRS. In this study, 50 patients with TRS, 45 patients with nontreatment-resistant schizophrenia (NTRS), 53 patients with schizophrenia at treatment initiation schizophrenia (TIS), and 90 healthy controls were enrolled. Serum NMDAR Ab levels and white matter diffusion tensor imaging fractional anisotropy (FA) were assessed. The white matter specificity effects by NMDAR Ab were assessed by comparing with effects on cortical and subcortical gray matter. Serum NMDAR Ab levels of the TRS were significantly higher than those of the NTRS (P = .035). In patients with TRS, higher NMDAR Ab levels were significantly associated with reduced whole-brain average FA (r = −.37; P = .026), with the strongest effect at the genu of corpus callosum (r = −.50; P = .0021, significant after correction for multiple comparisons). Conversely, there was no significant correlation between whole-brain or regional cortical thickness or any subcortical gray matter structural volume and NMDAR Ab levels in TRS. Our finding highlights a potential NMDAR mechanism on white matter microstructure impairment in schizophrenia that may contribute to their treatment resistance to antipsychotic medications.
... It is however not clear how SCZ specific NMDA alterations could impact on the system. The recent and seminal work of the group of Prof. Groc, using single molecule-based imaging shows that NMDA antibodies present in some SCZ patients with psychotic symptoms are specifically changing the surface dynamics and nanoscale organization of synaptic NMDA and its anchoring partner the EphrinB2 receptor in synaptic spines in hippocampal neurons, ultimately preventing LTP potentiation (Jezequel et al., 2017;Jezequel et al., 2018). As expected this causes a small reduction of the D1 surface expression in the same cellular system (Grea et al., 2019). ...
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Dopamine receptors are widely distributed within the brain where they play critical modulator roles on motor functions, motivation and drive, as well as cognition. The identification of five genes coding for different dopamine receptor subtypes, pharmacologically grouped as D1- (D1 and D5) or D2-like (D2S, D2L, D3, and D4) has allowed the demonstration of differential receptor function in specific neurocircuits. Recent observation on dopamine receptor signaling point at dopamine—glutamate-NMDA neurobiology as the most relevant in schizophrenia and for the development of new therapies. Progress in the chemistry of D1- and D2-like receptor ligands (agonists, antagonists, and partial agonists) has provided more selective compounds possibly able to target the dopamine receptors homo and heterodimers and address different schizophrenia symptoms. Moreover, an extensive evaluation of the functional effect of these agents on dopamine receptor coupling and intracellular signaling highlights important differences that could also result in highly differentiated clinical pharmacology. The review summarizes the recent advances in the field, addressing the relevance of emerging new targets in schizophrenia in particular in relation to the dopamine – glutamate NMDA systems interactions.
... The internalization of extrasynaptic NMDARs in the presence of autoantibodies is also observed in the presence of an NMDAR antagonist (93). Thus, NMDAR-Ab from patients with autoimmune encephalitis, as well as patients with mainly psychotic symptoms (94), impair the membrane dynamics and organization of NMDARs, shedding new light on the unexpected molecular mechanisms underpinning NMDAR dysfunction in major psychotic disorders such as schizophrenia. The detection of autoantibodies directed against other glutamatergic and GABAergic receptors in patients with various neurological and psychiatric conditions raises the possibility that autoantibodymediated neuropsychiatric symptoms are more widely mediated through disturbed membrane organization and dynamics of neurotransmitter receptors. ...
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Receptors moving in and out of the synapse The number of neurotransmitter receptors and their spatial organization on the postsynaptic site is a central determinant of synaptic efficacy. Sophisticated techniques to visualize and track the movement of single molecules have provided us with profound new insights into these dynamics. We now know that neurotransmitter receptors undergo movements on different scales. Groc and Choquet review our present understanding of the mechanisms that regulate glutamate receptor localization and clustering. Receptor movements are fundamental to basic synaptic function and participate in many forms of synaptic plasticity. Science , this issue p. eaay4631
... 25 Perhaps these collective characteristic descriptions represent the underlying mechanism of autoantibody-mediated, NMDAR-specific modulation. 4,26 Indeed, within early descriptions of NMDAR-antibody encephalitis, striking similarities were noted with other models of NMDARspecific disruption, 4 such as experimental and recreational use of phencyclidine and ketamine. 27 This hypothesised target-specific psycho pathology might therefore not translate to other autoantibody-mediated phenotypes. ...
Conference Paper
Objectives/Aims NMDAR-antibody encephalitis frequently presents with psychiatric symptoms. However, new-onset mental illness does not usually receive detailed biomedical investigations. Yet, early diagnosis and treatment correlates with improved outcomes. Here we used detailed psychiatric phenotyping to explore the nature of mental state abnormalities in this immunologically-defined illness. Methods Prospective and retrospective semi-structured interviews with patients, carers, and clinicians in five consecutive cases of definite NMDAR-antibody encephalitis (all female, median age=20 years, range=16–30, ovarian teratoma in 4). Weekly multi-disciplinary assessment using the Neuropsychiatric Inventory Nursing Home version (NPI-NH) in 2/5. Network analysis was used to evaluate connectedness of psychopathologic features and a qualitative synthesis distilled recurrent psychopathologic features. Finally, each time point was compared with operationalised diagnoses using an automated classifier and plotted with corresponding symptom complexes over time. Results All had psychiatric features at onset and were seen first by general practitioners or emergency departments. All received an incorrect initial diagnosis (1 neurological, 4 primary psychiatric). Two patients were referred to mental health services and detained while three were admitted to a general hospital. Psychiatric diagnoses spanned psychotic, mood, and stress categories. None had a personal or family history of serious mental illness or substance misuse. Despite the atypicality all were ascribed to non-specific psycho-social aetiologies. Autoimmune encephalitis was then first suspected between 4–28 days from onset (median=21 days) because of the psychopathology (n=2) or development of clear-cut seizures or movement disorder (n=3). 10 consistently reported features were identified: sleep disturbance, nightmares, mixed unstable mood, perplexity, incoherent repetitive speech, musical ±visual hallucinosis, catatonic facies, possession-like/drugged, dissociative-disorganised, and regressed behaviour.The symptom complex peaked rapidly (within 3 weeks). The peak burden was large and crossed multiple psychopathologic domains. Overall the syndrome is poorly-described by any single primary disorder; mixtures of mixed mood-psychotic-catatonic disorders performed best. Furthermore, it showed clear qualitative and hence diagnostic shifts between onset, peak, and resolution. Conclusions The psychopathology of NMDAR-antibody encephalitis is complex and dynamic, likely contributing to diagnostic difficulties. However, it appears stereotyped between individuals, hence sensitive features can be derived. Inconsistency with psychosis and/or mood disorder constructs and better approximation with ‘mixtures of mixtures’ suggests specificity is possible but similar studies with primary disorder comparators are needed. As the disease can only be ruled out with cerebrospinal fluid antibody testing the practical implication is that the mental health system needs to embrace lumbar puncture as a routine part of practice in high risk groups.
... 25 Perhaps these collective characteristic descriptions represent the underlying mechanism of autoantibody-mediated, NMDAR-specific modulation. 4,26 Indeed, within early descriptions of NMDAR-antibody encephalitis, striking similarities were noted with other models of NMDARspecific disruption, 4 such as experimental and recreational use of phencyclidine and ketamine. 27 This hypothesised target-specific psycho pathology might therefore not translate to other autoantibody-mediated phenotypes. ...
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Background Early immunotherapy administration improves outcomes in patients with N-methyl-D-aspartate receptor (NMDAR)-antibody encephalitis. As most patients with NMDAR-antibody encephalitis present to psychiatrists, the psychopathology of NMDAR-antibody encephalitis needs to be clearly defined to encourage accurate clinical identification and prompt treatment. Methods For this systematic review, we searched PubMed for all studies published in English between Jan 1, 2005, and Oct 7, 2017, to identify individually reported adult patients (≥18 years) who satisfied consensus criteria for definite NMDAR-antibody encephalitis. After generating a list of 50 fine-grained, lower-level features, we extracted psychopathological data in addition to demographic and aetiological data. The lower-level features were later ordered within higher-level categories. As a means of quality control, we filtered the data according to proxy markers of psychiatric involvement in their description. Subsequently, we compared lower-level features from individual patient data with operationalised psychiatric syndromes using a constrained combination approach and principal component analysis, and did a network analysis to explore the inter-relationships between multiple lower-level features. The review protocol was prospectively registered with PROSPERO, number CRD42017068981. Findings Of 1096 records identified in PubMed, 333 satisfied inclusion criteria and described 1100 patients in total with NMDAR-antibody encephalitis. The psychopathology of 505 (46%) patients with reported psychiatric symptoms was described in more detailed terms than only psychiatric or behavioural. 464 (91%) of the 505 patients were from papers in which patient data were reported individually. The remainder of the analyses focused exclusively on these 464 patients. Median age was 27 years (IQR 22–34), 368 (79%) of 464 patients were female and in 147 (32%), NMDAR-antibody encephalitis was associated with ovarian teratoma. The five higher-level categories into which the 464 patients most frequently grouped were behaviour (316 [68%]), psychosis (310 [67%]), mood (219 [47%]), catatonia (137 [30%]), and sleep disturbance (97 [21%]). The overall pattern of lower-level features was statistically stable across subgroups classified by age, sex, pregnancy association, presence of ovarian teratoma, prior herpes simplex virus encephalitis, and isolated psychiatric presentations (two-way ANOVA p=0·6–0·9). Constrained combination and principal component analyses found that mixtures of mood and psychosis syndromes fit each patient better than any single diagnosis alone, particularly for the patients in the psychiatric-described subgroup (mean ΔAkaike information criterion −0·04 in non-psychiatric-described subgroup vs 0·61 in psychiatric-described subgroup). The overlapping nature of the higher-level features was also enriched upon analysis of the psychiatric-described data (221 [67%] of 329 overlaps in non-psychiatric-described subgroup vs 96 [81%] of 118 overlaps in psychiatric-described subgroup, p=0·0052). Network analysis confirmed that the features were closely related and consistent between individual patients; the psychiatric-described subgroup had a markedly high and narrow range of closeness centralities (92% above 0·93 in psychiatric-described subgroup vs 51% above 0·93 in the non-psychiatric group). Interpretation The distinctive aspect of NMDAR-antibody encephalitis psychopathology is complexity; core aspects of mood and psychotic disorders consistently coexist within individual patients. Alongside the predominant young female demographic, these psychopathological features could help psychiatrists identify patients who would benefit from cerebrospinal fluid testing and immunotherapies. Well-controlled prospective studies with bespoke inventories are needed to advance this clinically grounded approach. Funding Wellcome Trust, NIHR Oxford Biomedical Research Centre, NIHR Oxford Health Biomedical Research Centre, British Medical Association Foundation for Medical Research.
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Neurodegenerative diseases (NDDs) are associated with the accumulation of a range of misfolded proteins across the central nervous system and related autoimmune responses, including the generation of antibodies and the activation of immune cells. Both innate and adaptive immunity become mobilized, leading to cellular and humoral effects. The role of humoral immunity in disease onset and progression remains to be elucidated with rising evidence suggestive of positive (protection, repair) and negative (injury, toxicity) outcomes. Herein, we review advances in research of neuron-targeting autoantibodies in the most prevalent NDDs. We discuss their biological origin, molecular diversity, and changes in the course of diseases, consider their relevance to the initiation and progression of pathology as well as diagnostic and prognostic significance. It is suggested that the emerging autoimmune aspects of NDDs not only could facilitate early detection but also might elucidate previously unknown facets of their pathobiology with relevance to the development of precision medicine. Graphical abstract: neurodegenerative diseases characterized with brain atrophy and breakdown of neurons lead to release and build-up of neuronal proteins, which activate autoimmune reaction and change in autoantibody activity in cerebrospinal fluid and peripheral circulation.
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Neurodevelopmental disorders such as those linked to intellectual disabilities or autism spectrum disorder are thought to originate in part from genetic defects in synaptic proteins. Single gene mutations linked to synapse dysfunction can broadly be separated in three categories: disorders of transcriptional dysregulation, disorders of synaptic signaling and disorders of synaptic scaffolding and structures. The recent developments in super-resolution imaging technologies and their application to synapses have unraveled a complex nanoscale organization of synaptic components. On the one hand, part of receptors, adhesion proteins, ion channels, scaffold elements and the pre-synaptic release machinery are partitioned in subsynaptic nanodomains, and the respective organization of these nanodomains has tremendous impact on synaptic function. For example, pre-synaptic neurotransmitter release sites are partly aligned with nanometer precision to postsynaptic receptor clusters. On the other hand, a large fraction of synaptic components is extremely dynamic and constantly exchanges between synaptic domains and extrasynaptic or intracellular compartments. It is largely the combination of the exquisitely precise nanoscale synaptic organization of synaptic components and their high dynamic that allows the rapid and profound regulation of synaptic function during synaptic plasticity processes that underlie adaptability of brain function, learning and memory. It is very tempting to speculate that genetic defects that lead to neurodevelopmental disorders and target synaptic scaffolds and structures mediate their deleterious impact on brain function through perturbing synapse nanoscale dynamic organization. We discuss here how applying super-resolution imaging methods in models of neurodevelopmental disorders could help in addressing this question.
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Introduction N-methyl-d-aspartate receptor antibody (NMDAR-Ab) encephalitis consensus criteria has recently been defined. We aimed to examine the prevalence of NMDAR-Ab encephalitis in patients with first episode psychosis (FEP) and treatment resistant schizophrenia (TRS) on clozapine, using clinical investigations, antibody testing and to retrospectively apply diagnostic consensus criteria. Methods Adult (18-65 years old) cases of FEP meeting inclusion criteria were recruited over three years and assessed using SCID. NMDAR-Ab was identified using a live cell-based assay (L-CBA). Seropositive cases were clinically investigated for features of encephalitis including CSF where possible. Serum was retested using immunohistochemistry (IHC) as part of diagnostic criteria guidelines. A cohort of patients with TRS was also recruited. Results 112 FEP patients were recruited over 3 years. NMDAR-Ab seroprevalence was 4/112 (3.5%) cases. One case (<1%) was diagnosed with definite NMDAR-Ab encephalitis and treated with immunotherapy. One of the three other seropositive cases met criteria for probable encephalitis. However all three were ultimately diagnosed with mood disorders with psychotic features. None have developed neurological features at three year follow up. 1/100 (1%) of patients with TRS was seropositive for NMDAR-Ab but did not meet criteria for encephalitis. Conclusions NMDAR-Ab encephalitis as defined by consensus guidelines occured rarely in psychiatric services in this study. Further studies are needed to establish pathogenicity of serum NMDAR-Ab antibodies. Psychiatric services should be aware of the clinical features of encephalitis.
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The subunit composition of synaptic NMDA receptors (NMDAR), such as the relative content of GluN2A- and GluN2B-containing receptors, greatly influences the glutamate synaptic transmission. Receptor co-agonists, glycine and D-serine, have intriguingly emerged as potential regulators of the receptor trafficking in addition to their requirement for its activation. Using a combination of single-molecule imaging, biochemistry and electrophysiology, we show that glycine and D-serine relative availability at rat hippocampal glutamatergic synapses regulate the trafficking and synaptic content of NMDAR subtypes. Acute manipulations of co-agonist levels, both ex vivo and in vitro, unveil that D-serine alter the membrane dynamics and content of GluN2B-NMDAR, but not GluN2A-NMDAR, at synapses through a process requiring PDZ binding scaffold partners. In addition, using FRET-based FLIM approach, we demonstrate that D-serine rapidly induces a conformational change of the GluN1 subunit intracellular C-terminus domain. Together our data fuels the view that the extracellular microenvironment regulates synaptic NMDAR signaling. DOI: http://dx.doi.org/10.7554/eLife.25492.001
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Autoantibodies of the IgG class against N-methyl-D-aspartate-receptor subunit-NR1 (NMDAR1-AB) were considered pathognomonic for anti-NMDAR encephalitis. This view has been challenged by the age-dependent seroprevalence (up to >20%) of functional NMDAR1-AB of all immunoglobulin classes found in >5000 individuals, healthy or affected by different diseases. These findings question a merely encephalitogenic role of NMDAR1-AB. Here, we show that NMDAR1-AB belong to the normal autoimmune repertoire of dogs, cats, rats, mice, baboons, and rhesus macaques, and are functional in the NMDAR1 internalization assay based on human IPSC-derived cortical neurons. The age dependence of seroprevalence is lost in nonhuman primates in captivity and in human migrants, raising the intriguing possibility that chronic life stress may be related to NMDAR1-AB formation, predominantly of the IgA class. Active immunization of ApoE−/− and ApoE+/+ mice against four peptides of the extracellular NMDAR1 domain or ovalbumin (control) leads to high circulating levels of specific AB. After 4 weeks, the endogenously formed NMDAR1-AB (IgG) induce psychosis-like symptoms upon MK-801 challenge in ApoE−/− mice, characterized by an open blood–brain barrier, but not in their ApoE+/+ littermates, which are indistinguishable from ovalbumin controls. Importantly, NMDAR1-AB do not induce any sign of inflammation in the brain. Immunohistochemical staining for microglial activation markers and T lymphocytes in the hippocampus yields comparable results in ApoE−/− and ApoE+/+ mice, irrespective of immunization against NMDAR1 or ovalbumin. These data suggest that NMDAR1-AB of the IgG class shape behavioral phenotypes upon access to the brain but do not cause brain inflammation on their own.
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Circulating autoantibodies against glutamatergic N-methyl-D-aspartate receptor (NMDAR-Ab) have been reported in a proportion of patients with psychotic disorders, raising hopes for more appropriate treatment for these antibody-positive patients. However, the prevalence of circulating NMDAR-Ab in psychotic disorders remains controversial with detection prevalence rates, and immunoglobulin (Ig) classes, varying considerably between studies, perhaps because of different detection methods. Here, we compared the results of serum assays for a large cohort of first episode psychosis patients (FEP) using classical cell-based assays in three labs and a single molecule-based imaging method. Most assays and single molecule imaging in live hippocampal neurons revealed the presence of circulating NMDAR-Ab in approximately 5% of FEP patients. However, some heterogeneity between cell-based assays was clearly observed, highlighting the urgent need of new sensitive methods to detect the presence of low-titer NMDAR-Ab in seropositive patients that cannot be clinically identified from seronegative ones.
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Autoimmune encephalitis (AE) mediated by antibodies against synaptic and neuronal surface targets frequently presents with a psychiatric syndrome. In these patients, removal of autoantibodies treats the disease and outcomes are closely linked to early intervention. The discovery of these autoantibodies in isolated psychiatric syndromes has raised the possibility that these patients may derive similar benefits from immunotherapy, a potentially transformational approach to the treatment of mental illness. Although open-label case series suggest impressive therapeutic outcomes, the pathological relevance of these autoantibodies outside of canonical presentations is debated. The advent of diagnostic criteria for AE attempts to facilitate its prompt identification but risks prematurely neglecting the potential scientific and clinical significance of isolated syndromes that do not satisfy these criteria. Here, we propose using a syndrome-level taxonomy that has occasional, but not necessary, overlap with AE: synaptic and neuronal autoantibody-associated psychiatric syndromes or “SNAps”. This will prevent confusion with AE and act heuristically to promote active investigation into this rare example of psychopathology defined on a molecular level. We suggest that this concept would have application in other autoantibody-associated syndromes including seizure, cognitive, and movement disorders, in which similar issues arise. We review putative direct and indirect mechanisms and outline experimentally testable hypotheses that would help to determine prospectively in whom autoantibody detection is relevant, and as important, in whom it is not. We summarize a pragmatic approach to autoantibody testing and management in severe mental illness in order to promptly diagnose AE and advocate a research-orientated experimental medicine paradigm for SNAps, where there is greater equipoise. We conclude that SNAps remains a nascent area of clinical neuroscience with great potential and in ongoing need of psychiatry-led basic and clinical research.
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N-methyl-d-aspartate receptors (NMDARs) are ion channels whose synaptic versus extrasynaptic localization critically influences their functions. This distribution of NMDARs is highly dependent on their lateral diffusion at the cell membrane. Each obligatory subunit of NMDARs (GluN1 and GluN2) contains two extracellular clamshell-like domains with an agonist-binding domain and a distal N-terminal domain (NTD). To date, the roles and dynamics of the NTD of the GluN1 subunit in NMDAR allosteric signaling remain poorly understood. Using single nanoparticle tracking in mouse neurons, we demonstrate that the extracellular neuronal protease tissue-type plasminogen activator (tPA), well known to have a role in the synaptic plasticity and neuronal survival, leads to a selective increase of the surface dynamics and subsequent diffusion of extrasynaptic NMDARs. This process explains the previously reported ability of tPA to promote NMDAR-mediated calcium influx. In parallel, we developed a monoclonal antibody capable of specifically blocking the interaction of tPA with the NTD of the GluN1 subunit of NMDAR. Using this original approach, we demonstrate that the tPA binds the NTD of the GluN1 subunit at a lysine in position 178. Accordingly, when applied to mouse neurons, our selected antibody (named Glunomab) leads to a selective reduction of the tPA-mediated surface dynamics of extrasynaptic NMDARs, subsequent signaling and neurotoxicity, both in vitro and in vivo. Altogether, we demonstrate that the tPA is a ligand of the NTD of the obligatory GluN1 subunit of NMDAR acting as a modulator of their dynamic distribution at the neuronal surface and subsequent signaling.
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Background The diagnostic scheme for psychiatric disorders is currently based purely on descriptive nomenclature given that biomarkers subtypes and clearly defined causal mechanisms are lacking for the vast majority of disorders. The emerging field of “immuno-psychiatry” has the potential to widen the exploration of a mechanism-based nosology, possibly leading to the discovery of more effective personalised treatment strategies. Discussion Disturbances in immuno-inflammatory and related systems have been implicated in the aetiology, pathophysiology, phenomenology and comorbidity of several psychiatric disorders, including major mood disorders and schizophrenia. A fundamental challenge in their clinical management is to identify bio-signatures that might indicate risk, state, trait, prognosis or theragnosis. Here, we provide the rationale for a clinical and research agenda to refine future clinical practice and conceptual views, and to delineate pathways toward innovative treatment discovery. Conclusion The development of bio-signatures will allow clinicians to tailor interventions to the abovementioned biomarker subtypes – a major translational goal for research in this field.
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Autoantibodies of the IgG class against N-methyl-d-aspartate-receptor subunit NR1 (NMDAR1) were first described in anti-NMDAR encephalitis and seen as disease indicators. Recent work on together over 5000 individuals challenged this exclusive view by showing age-dependently up to >20% NMDAR1-autoantibody seroprevalence with comparable immunoglobulin class and titer distribution across health and disease. The key question therefore is to understand the properties of these autoantibodies, also in healthy carriers, in order to assess secondary complications and possible contributions to neuropsychiatric disease. Here, we believe we provide for human NMDAR1-autoantibodies the first comprehensive analysis of their target epitopes and functionality. We selected sera of representative carriers, healthy or diagnosed with very diverse conditions, that is, schizophrenia, age-related disorders like hypertension and diabetes, or anti-NMDAR encephalitis. We show that all positive sera investigated, regardless of source (ill or healthy donor) and immunoglobulin class, provoked NMDAR1 internalization in human-induced pluripotent stem cell-derived neurons and reduction of glutamate-evoked currents in NR1-1b/NR2A-expressing Xenopus oocytes. They displayed frequently polyclonal/polyspecific epitope recognition in the extracellular or intracellular NMDAR1 domains and some additionally in NR2A. We conclude that all circulating NMDAR1-autoantibodies have pathogenic potential regarding the whole spectrum of neuronal NMDAR-mediated effects upon access to the brain in situations of increased blood-brain-barrier permeability.Molecular Psychiatry advance online publication, 9 August 2016; doi:10.1038/mp.2016.125.
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Introduction: Immune dysregulation is suggested to play an important aetiological role in schizophrenia (SZ) and bipolar disorder (BD) potentially driving neurodevelopmental pathways. Immune dysfunction may precede the onset of psychiatric disorders and parallel the development of multiaxial comorbidity, including suicidal behaviour and metabolic and autoimmune disorders. Depicting the source of the chronic low-grade inflammatory component in SZ and BD is thus a research priority. Strong environmental insults early in life, such as infections, acting on a background of genetic vulnerability, may induce potent and enduring inflammatory responses setting a state of liability to second-hit environmental encounters, namely childhood trauma, drug abuse or additional infectious exposures. The immunogenetic background of susceptibility, suggested to be not only lying within the HLA locus but also implicating inherited deficits of the innate immune system, may amplify the harmful biological effects of infections/psychosocial stress leading to the manifestation of a broad range of psychiatric symptoms. Objectives: The present review aims to discuss the following: (i) biological arguments in favour of a chronic low-grade inflammation in SZ and BD and its potential origin in the interaction between the immunogenetic background and environmental infectious insults, and (ii) the consequences of this inflammatory dysfunction by focusing on N-methyl-D-aspartate (NMDA) receptor antibodies and activation of the family of human endogenous retroviruses (HERVs). Conclusions: Specific therapeutic approaches targeting immune pathways may lead the way to novel personalized medical interventions, improvement of quality of life and average life expectancy of psychiatric patients, if not even prevent mood episodes and psychotic symptoms.
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Background: Identification of patients at high risk of treatment-resistant schizophrenia at the time of schizophrenia diagnosis would be of great clinical benefit in minimising the delay to clozapine treatment in patients unlikely to respond to non-clozapine antipsychotics. However, little is known about predictors of treatment resistance in this patient population. We used a treatment-based proxy for treatment-resistant schizophrenia to identify candidate predictors of treatment resistance at first hospital contact with a schizophrenia diagnosis. Methods: In this population-based cohort study, we obtained Danish national registry data for all adult patients (≥18 years) with incident schizophrenia diagnosed between Jan 1, 1996, and Dec 31, 2006, and followed up until Dec 31, 2010. Our main proxy definition of treatment-resistant schizophrenia was the earliest instance of either clozapine initiation or hospital admission for schizophrenia after having had two periods of different antipsychotic monotherapy. We did multivariable Cox proportional hazards regression analysis to estimate the association between baseline candidate predictors and treatment resistance. Findings: 8624 patients fulfilled the criteria for inclusion. In multivariable complete-case analyses, 1703 (21%) of 8044 patients fulfilled the main proxy definition of treatment-resistant schizophrenia during a median follow-up of 9·1 years (IQR 6·3-11·9). Younger age (hazard ratio 0·96 [95% CI 0·95-0·97]), living in a less urban area (provincial 1·38 [1·23-1·56], rural 1·44 [1·25-1·65]), primary education level (0·88 [0·79-0·98]), more than 30 bed-days in psychiatric hospital in the year before first schizophrenia diagnosis (1·54 [1·35-1·75]), inpatient at first schizophrenia diagnosis (2·07 [1·87-2·29]), paranoid subtype (1·24 [1·13-1·37]), comorbid personality disorder (1·24 [1·11-1·39]), psychotropic drug use (antipsychotics 1·51 [1·35-1·69], antidepressants 1·15 [1·03-1·29], and benzodiazepines 1·22 [1·10-1·37]), and previous suicide attempt (1·21 [1·07-1·39]) were all significantly associated with treatment-resistant schizophrenia. Interpretation: Our study identifies several candidate predictors that could potentially be included in future prediction models for treatment-resistant schizophrenia. Notably, established risk factors for schizophrenia did not predict treatment resistance, suggesting that treatment-resistant disease might be a distinct subtype of schizophrenia and not merely a more severe form. Funding: European Community's Seventh Framework Programme.
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Rationale: Autoantibodies to central nervous system (CNS) neuronal surface antigens have been described in association with autoimmune encephalopathies which prominently feature psychiatric symptoms in addition to neurological symptoms. The potential role of these autoantibodies in primary psychiatric diseases such as schizophrenia or bipolar affective disorder is of increasing interest. Objectives: We aimed to review the nature of psychiatric symptoms associated with neuronal surface autoantibodies, in the context of autoimmune encephalopathies as well as primary psychiatric disorders, and to review the mechanisms of action of these autoantibodies from a psychopharmacological perspective. Results: The functional effects of the autoantibodies on their target antigens are described; their clinical expression is at least in part mediated by their effects on neuronal receptor function, primarily at the synapse, usually resulting in receptor hypofunction. The psychiatric effects of the antibodies are related to known functions of the receptor target or its complexed proteins, with reference to supportive genetic and pharmacological evidence where relevant. Evidence for a causal role of these autoantibodies in primary psychiatric disease is increasing but remains controversial; relevant methodological controversies are outlined. Non-receptor-based mechanisms of autoantibody action, including neuroinflammatory mechanisms, and therapeutic implications are discussed. Conclusions: An analysis of the autoantibodies from a psychopharmacological perspective, as endogenous, bioactive, highly specific, receptor-targeting molecules, provides a valuable opportunity to understand the neurobiological basis of associated psychiatric symptoms. Potentially, new treatment strategies will emerge from the improving understanding of antibody-antigen interaction within the CNS.
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Immunological mechanisms and therapy approaches in psychotic syndromes were recently supported by the discovery of autoantibody-associated limbic and non-limbic encephalitis. However, how clinical diagnostic procedures in psychiatry should be adapted to these new insights is still unclear. In this study, we analyzed the cerebrospinal fluid (CSF) and neuroimmunological alterations and their association with cerebral MRI (cMRI) and electroencephalographic (EEG) findings. From 2006 to 2013, we acquired 180 CSF samples from psychotic patients. Between 2006 and 2009, CSF examinations were only performed in cases in which organic brain disease was suspected. Since then, this procedure has been integrated into our routine diagnostic workup. CSF basic diagnostics were supplemented by measuring antineuronal antibodies against intracellular synaptic antigens, antibodies against intracellular onconeural antigens, antibodies against neuronal cell surface antigens and thyroid antibodies. In addition, cMRIs and EEGs were conducted. We found white cell counts elevated in 3.4% of the cases, albumin quotient elevated in 21.8%, and protein concentration elevated in 42.2%. Evidence of intrathecal immunoglobulin synthesis was found in 7.2% of the cases. Antibodies measured against neuronal cell surface antigens were positive in 3.2%. Reactivity on antibodies against intracellular onconeural antigens were detected in 3.5%. Serum thyroid antibodies were elevated in 24.7%. Abnormalities were found in 39.5% of cMRIs and in 34.3% of EEGs. The main finding of our study was the high prevalence of CSF and autoantibody abnormalities in 54.4% of psychotic patients. In combination with cMRIs and EEGs, 75.6% showed abnormal findings. Our results are discussed with regard to the concept of immunological encephalopathy. Future studies should analyze the efficacy of immunomodulatory therapies.
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Background Encephalitis with antibodies against N-methyl-D-aspartate receptor (NMDA-R) is classified as an autoimmune disorder with psychotic symptoms, which are frequently dominant. However, it remains unclear how frequently NMDA-R antibodies lead to a condition that mimics psychosis and first-episode schizophrenia. In our work, we investigated the presence of antibodies against NMDA-R in patients with first-episode psychosis (FEP) in comparison with healthy volunteers. Methods This study included 50 antipsychotic-naïve patients with FEP (including 21 women) and 50 healthy volunteers (including 21 women). The mean age of the patients was 27.4 (±7.4) years and that of the healthy controls was 27.0 (±7.3) years. Antibodies against NMDA-R in the serum were detected by immunofluorescence. Results None of the investigated patients with an FEP and none of the healthy controls showed positive antibodies against NMDA-Rs. Conclusion According to results of studies, a small proportion of patients with an FEP possess antibodies against NMDA-R. However, the extent to which this finding contributes to the etiopathogenesis of the response to antipsychotic medication and whether immunomodulatory therapy is indicated in these cases remains uncertain.
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N-methyl-d-aspartate receptor (NMDA-R) autoantibodies have been reported in people with acute psychosis. We hypothesised that their presence may be implicated in the aetiology of treatment-refractory psychosis. We sought to ascertain the point prevalence of NMDA-R antibody positivity in patients referred to services for treatment-refractory psychosis. We found that 3 (7.0%) of 43 individuals had low positive NMDA-R antibody titres. This suggests that NMDA-R autoantibodies are unlikely to account for a large proportion of treatment-refractory psychosis. Royal College of Psychiatrists.
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In 2007, serum IgG autoantibodies to the NMDAR (NMDAR-Ab) were identified in subjects with an autoimmune encephalopathy responsive to immunotherapy; two thirds of whom present with psychiatric symptoms (Dalmau et al., 2007, Irani et al., 2010 and Titulaer et al., 2013). There is increasing evidence for NMDAR-hypofunction and neuroinflammation in the pathophysiology of first episode schizophrenia (Kahn and Sommer, 2014). Whilst many patients with NMDAR-ab develop a widespread encephalopathy, restricted phenotypes, including isolated psychosis, epilepsy, or movement disorders have also been described (Irani et al., 2010, Zandi et al., 2011, Brenner et al., 2013, Titulaer et al., 2013 and Hacohen et al., 2014). We reported in 2010 for the first time IgG NMDAR, and voltage gated potassium channel-complex (VGKC), antibodies in 3 of 46 (6.5%) patients with a first episode psychosis without other neurological symptoms (Zandi et al., 2011). Pollak and colleagues, found IgG NMDAR-ab in 1.46% (95% CI 0.94–2.23) cases of psychosis and schizophrenia from 7 studies, compared to (5/1598) 0.3% controls, but a variety of assays including fixed assays were compared (Pollak et al., 2013). In their analysis, rates of IgA and IgM antibodies were higher in both cases (7.1%) and controls (10.2%), though IgA and IgM antibodies are of unlikely pathogenic relevance. Dalmau and colleagues found isolated psychotic episodes in 23/571 (4%) patients with NMDAR-Ab encephalitis either in presentation (5) or at relapse (18) (Kayser et al., 2013). One test of clinical relevance of autoantibodies is the immunotherapy response. Here we describe 18 cases of acute psychosis with NMDAR-ab measured by live cell based assay without clear clinical ‘neurological’ involvement, 9 of whom we treated with immunotherapy.
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Anti-N-methyl D-aspartate receptor (NMDAR) encephalitis is a severe neuropsychiatric disorder that associates with prominent memory and behavioural deficits. Patients' antibodies react with the N-terminal domain of the GluN1 (previously known as NR1) subunit of NMDAR causing in cultured neurons a selective and reversible internalization of cell-surface receptors. These effects and the frequent response to immunotherapy have suggested an antibody-mediated pathogenesis, but to date there is no animal model showing that patients' antibodies cause memory and behavioural deficits. To develop such a model, C57BL6/J mice underwent placement of ventricular catheters connected to osmotic pumps that delivered a continuous infusion of patients' or control cerebrospinal fluid (flow rate 0.25 µl/h, 14 days). During and after the infusion period standardized tests were applied, including tasks to assess memory (novel object recognition in open field and V-maze paradigms), anhedonic behaviours (sucrose preference test), depressive-like behaviours (tail suspension, forced swimming tests), anxiety (black and white, elevated plus maze tests), aggressiveness (resident-intruder test), and locomotor activity (horizontal and vertical). Animals sacrificed at Days 5, 13, 18, 26 and 46 were examined for brain-bound antibodies and the antibody effects on total and synaptic NMDAR clusters and protein concentration using confocal microscopy and immunoblot analysis. These experiments showed that animals infused with patients' cerebrospinal fluid, but not control cerebrospinal fluid, developed progressive memory deficits, and anhedonic and depressive-like behaviours, without affecting other behavioural or locomotor tasks. Memory deficits gradually worsened until Day 18 (4 days after the infusion stopped) and all symptoms resolved over the next week. Accompanying brain tissue studies showed progressive increase of brain-bound human antibodies, predominantly in the hippocampus (maximal on Days 13-18), that after acid extraction and characterization with GluN1-expressing human embryonic kidney cells were confirmed to be against the NMDAR. Confocal microscopy and immunoblot analysis of the hippocampus showed progressive decrease of the density of total and synaptic NMDAR clusters and total NMDAR protein concentration (maximal on Day 18), without affecting the post-synaptic density protein 95 (PSD95) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. These effects occurred in parallel with memory and other behavioural deficits and gradually improved after Day 18, with reversibility of symptoms accompanied by a decrease of brain-bound antibodies and restoration of NMDAR levels. Overall, these findings establish a link between memory and behavioural deficits and antibody-mediated reduction of NMDAR, provide the biological basis by which removal of antibodies and antibody-producing cells improve neurological function, and offer a model for testing experimental therapies in this and similar disorders.
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Abstract Objective There are now a large number of requests for N-methyl-d-aspartate receptor autoantibody (NMDAR-Ab) tests, and it is important to assess the clinical relevance of all results, particularly when they are reported as ‘Low Positive’. Methods The clinical data of 56 patients found Positive or Low Positive by the Oxford live cell-based assay were reviewed. An autoimmune basis for the condition was assigned as ‘Definite’, ‘Possible’ or ‘Unlikely’. The number of core features (encephalopathy, psychiatric, cognitive, epileptic, extrapyramidal and inflammatory cerebrospinal fluid (CSF)) was tabulated. Results Twenty-five (44.6%) patients had a Definite NMDAR-Ab encephalitis (eight ovarian teratomas, one Hodgkin's lymphoma), 18 (32.1%) a Possible NMDAR-Ab encephalitis and 13 (23.2%) an Unlikely autoimmune syndrome. Serum NMDAR-Ab levels were higher in patients with tumours. Positive NMDAR-Abs were found not only in patients with three or more core features and a Definite syndrome, but also in five patients classified as Possible. Conversely, Low Positive NMDAR-Abs were present in 7 Definite cases as well as in 13 Possible cases. Unlikely patients had mainly Low Positive antibodies and fewer core features. CSF NMDAR-Abs, only available in 11 pairs and at varying time points, broadly related to serum levels and were Positive in 3/3 patients with tumours but in only 2/5 Definite patients, and none of the Possible or Unlikely cases. Interpretation Using live cell-based assays, Positive and Low Positive antibodies can be of clinical significance. The number of core clinical features should help to select those patients in whom an immunotherapy intervention might be considered, irrespective of the antibody level.
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Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
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Recent large-scale genomic studies have revealed two broad classes of risk alleles for schizophrenia: a polygenic component of risk mediated through multiple common risk variants and rarer more highly penetrant sub-microscopic chromosomal deletions and duplications, known as copy number variants. The focus of this review is on the emerging findings from the latter and subsequent exome sequencing data of smaller, deleterious single nucleotide variants and indels. In these studies schizophrenia patients were found to have enriched de novo mutations in genes belonging to the post synaptic density at glutamatergic synapses, particularly components of the NMDA receptor signalling complex including the PSD-95 complex, ARC interactors, the FMRP complex, voltage-gated calcium channels and genes implicated in actin cytoskeletal dynamics. The convergence of these implicated genes onto a coherent biological pathway at the synapse, with a specific role in plasticity, provides a significant advance in understanding pathogenesis and point to new targets for biological investigation. We consider the implications of these studies in the context of existing genetic data and the potential need to reassess diagnostic boundaries of neuropsychiatric disorders, before discussing ways forward for more directed mechanistic studies in order to develop stratified, novel therapeutic approaches in the future.
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Objective A severe but treatable form of immune-mediated encephalitis is associated with antibodies in serum and cerebrospinal fluid (CSF) against the GluN1 subunit of the N-methyl-D-aspartate receptor (NMDAR). Prolonged exposure of hippocampal neurons to antibodies from patients with anti-NMDAR encephalitis caused a reversible decrease in the synaptic localization and function of NMDARs. However, acute effects of the antibodies, fate of the internalized receptors, type of neurons affected, and whether neurons develop compensatory homeostatic mechanisms were unknown and are the focus of this study. Methods Dissociated hippocampal neuron cultures and rodent brain sections were used for immunocytochemical, physiological, and molecular studies. Results Patient antibodies bind to NMDARs throughout the rodent brain, and decrease NMDAR cluster density in both excitatory and inhibitory hippocampal neurons. They rapidly increase the internalization rate of surface NMDAR clusters, independent of receptor activity. This internalization likely accounts for the observed decrease in NMDAR-mediated currents, as no evidence of direct blockade was detected. Once internalized, antibody-bound NMDARs traffic through both recycling endosomes and lysosomes, similar to pharmacologically induced NMDAR endocytosis. The antibodies are responsible for receptor internalization, as their depletion from CSF abrogates these effects in hippocampal neurons. We find that although anti-NMDAR antibodies do not induce compensatory changes in glutamate receptor gene expression, they cause a decrease in inhibitory synapse density onto excitatory hippocampal neurons. Interpretation Our data support an antibody-mediated mechanism of disease pathogenesis driven by immunoglobulin-induced receptor internalization. Antibody-mediated downregulation of surface NMDARs engages homeostatic synaptic plasticity mechanisms, which may inadvertently contribute to disease progression. Ann Neurol 2014;76:108–119
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Molecular Psychiatry publishes work aimed at elucidating biological mechanisms underlying psychiatric disorders and their treatment
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BACKGROUND: N-methyl-d-aspartate receptor (NMDAR) antibodies have been documented in the serum of individuals with primary psychiatric disorders from several independent cohorts, but these findings have not been systematically assessed in aggregate or in relation to methodological covariates. METHODS: We searched MEDLINE, EMBASE, and PsycINFO for studies in any language that provided data on NMDAR antibody seropositivity or absolute serum titers in schizophrenia or schizoaffective, bipolar, or major depressive disorders. We used a random effects model to pool estimates across studies. RESULTS: Nine studies met the eligibility criteria. Five studies (3387 participants) provided data on NMDAR antibody seropositivity in psychiatric versus control groups based on high-specificity seropositivity thresholds (cell-based assays [CBAs]: 1:320 dilution, 1:200 dilution, visual score>1; enzyme-linked immunosorbent assay [ELISA]: 90(th) percentile of control titers). Meta-analysis showed significantly higher odds of NMDAR antibody seropositivity among those with schizophrenia or schizoaffective, bipolar, or major depressive disorders compared with healthy controls (odds ratio [OR], 3.10; 95% confidence interval [CI], 1.04-9.27; P=.043; I(2)=68%). Four studies (3194 participants) provided outcome data for these groups based on low-specificity seropositivity thresholds (CBAs 1:10 dilution; ELISA: 75(th) percentile of control titers). Meta-analysis showed greater heterogeneity and no significant between-group difference (OR, 2.31; 95% CI, 0.55-9.73; P=.25; I(2)=90%). Seropositive participants in psychiatric groups had various combinations of IgG, IgM, and IgA class antibodies against NR1, NR1/NR2B, and NR2A/NR2B subunits. Subgroup analysis revealed significantly higher odds of seropositivity among all participants based on 1:10 versus 1:320 dilution seropositivity thresholds (OR, 4.56; 95% CI, 2.41-8.62; P<.001; I(2)=0%; studies=2, n=2920), but no apparent difference between first-episode and chronic schizophrenia or schizoaffective disorder (OR, 1.15; 95% CI, 0.19-7.24; P=.88, I(2)=43%, studies=2, n=1108). Average NR2A/NR2B antibody titers determined by ELISA were significantly higher among participants with first-episode schizophrenia (P<.0001) and acute mania (P<.01) compared with healthy controls. Levels decreased by 58% at 8weeks in first-episode schizophrenia, and by about 13% at 4days in acute mania. CONCLUSIONS: Individuals with schizophrenia or schizoaffective, bipolar, or major depressive disorders are collectively about three times more likely to have elevated NMDAR antibody titers compared with healthy controls based on high-specificity, but not low-specificity, seropositivity thresholds, though considerable methodological and statistical heterogeneity exists. Evidence concerning the effect of disease state and time of serum acquisition is varied and consistent, respectively. Adequately powered longitudinal studies employing standardized assay methods and seropositivity threshold definitions, and quantifying NMDAR antibodies in both sera and cerebrospinal fluid are needed to further elucidate the clinical and pathophysiological implications of this association. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved. KEYWORDS: Antibodies; Bipolar disorder; Immunoglobulin; Major depressive disorder; Meta-analysis; N-methyl-d-aspartate receptor; Psychoimmunology; Schizoaffective disorder; Schizophrenia; Systematic review
Article
Background: Anti-N-Methyl-D-Aspartate receptor (NMDAR) encephalitis is an autoimmune disorder that often affects women of childbearing age, and maternal-fetal transfer of anti-NMDAR antibodies during pregnancy has been documented in both symptomatic and asymptomatic women. The effects of these antibodies on the fetus, however, are incompletely understood. Patient description: This term infant exhibited depressed respiratory effort, poor feeding, and abnormal movements after birth. Magnetic resonance imaging revealed diffuse cerebral edema with ischemic and hemorrhagic injury. Her mother had experienced anti-NMDAR encephalitis secondary to an ovarian teratoma 18 months earlier. The baby's serum NMDAR antibody titer was elevated at 1:320. Intravenous immunoglobulin did not result in clinical improvement, and care was withdrawn on day of life 20. Her mother had an elevated serum NMDAR antibodies (1:80), positive CSF antibody titers, and a new ovarian teratoma. Conclusion: Routine testing of NMDAR antibodies in pregnant women with a previous history of anti-NMDAR encephalitis may be warranted. Infants born to these mothers should be closely monitored throughout pregnancy and after birth.
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Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here, we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain providing biological plausibility for the findings. Many findings have the potential to provide entirely novel insights into aetiology, but associations at DRD2 and multiple genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that play important roles in immunity, providing support for the hypothesized link between the immune system and schizophrenia.
Article
Autoimmune encephalopathy caused by autoantibodies against neuronal cell-surface proteins in the brain is a newly discovered disease category associated with psychiatric disorders. Correct diagnosis of this condition relies on the detection of specific autoantibodies in the blood or cerebral spinal fluid in addition to the clinical presentations. The study aimed to understand the seroprevalence of selective anti-neuronal autoantibodies in our patients with schizophrenia. First, we screened for six anti-neuronal autoantibodies in an archived blood sample collected from patients with the first-episode schizophrenia. The six autoantibodies including antibodies against N-methyl-d-aspartate (NMDA) receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors 1 and 2, γ-butyric acid receptor type B1 (GABARB1), leucine-rich glioma inactivated-1 (LGI1) protein, and contactin-associated protein-like 2 (CASPR2) protein. A total of 78 plasma samples (46 males and 32 females) were investigated; however, no positive case was identified. In this second study, we screened anti-NMDA receptor autoantibodies in a blood sample of 234 patients with chronic schizophrenia (133 females and 101 males) including 48 patients defined as treatment resistance. None of this sample was detected as positive. The negative findings in this study suggest that the seroprevalence of autoantibodies against neuronal surface proteins might be low in patients diagnosed with schizophrenia.
Article
Background: Psychosis is a common presenting feature in antibody-mediated encephalitis, for which prompt recognition and treatment usually leads to remission. We aimed to investigate whether people with circumscribed schizophrenia-like illnesses have such antibodies-especially antibodies against the N-methyl-D-aspartate receptor (NMDAR)-more commonly than do healthy controls. Methods: We recruited patients aged 14-35 years presenting to any of 35 mental health services sites across England with first-episode psychosis, less than 6 weeks of treatment with antipsychotic medication, and a score of 4 or more on at least one selected Positive and Negative Syndrome Scale (PANSS) item. Patients and controls provided venous blood samples. We completed standardised symptom rating scales (PANSS, ACE-III, GAF) at baseline, and tested serum samples for antibodies against NMDAR, LGI1, CASPR2, the GABAA receptor, and the AMPA receptor using live cell-based assays. Treating clinicians assessed outcomes of ICD diagnosis and functioning (GAF) at 6 months. We included healthy controls from the general population, recruited as part of another study in Cambridge, UK. Findings: Between Feb 1, 2013, and Aug 31, 2014, we enrolled 228 patients with first-episode psychosis and 105 healthy controls. 20 (9%) of 228 patients had serum antibodies against one or more of the neuronal cell surface antibodies compared with four (4%) of 105 controls (unadjusted odds ratio 2·4, 95% CI 0·8-7·3). These associations remained non-significant when adjusted for current cigarette smoking, alcohol consumption, and illicit drug use. Seven (3%) patients had NMDAR antibodies compared with no controls (p=0·0204). The other antibodies did not differ between groups. Antibody-positive patients had lower PANSS positive, PANSS total, and catatonia scores than did antibody-negative patients. Patients had comparable scores on other PANSS items, ACE-III, and GAF at baseline, with no difference in outcomes at 6 months. Interpretation: Some patients with first-episode psychosis had antibodies against NMDAR that might be relevant to their illness, but did not differ from patients without NMDAR antibodies in clinical characteristics. Our study suggests that the only way to detect patients with these potentially pathogenic antibodies is to screen all patients with first-episode psychosis at first presentation. Funding: Medical Research Council.
Article
View largeDownload slide See Zekeridou and Lennon (doi: 10.1093/aww213 ) for a scientific commentary on this article . Antibodies against the NR1 subunit of the NMDA receptor are suspected to underlie anti-NMDA receptor encephalitis. Kreye et al. provide direct evidence by showing that monoclonal human NR1 antibodies are sufficient to downregulate synaptic NMDA receptors. They show too that patients harbour a much broader auto-antibody repertoire than previously thought. View largeDownload slide See Zekeridou and Lennon (doi: 10.1093/aww213 ) for a scientific commentary on this article . Antibodies against the NR1 subunit of the NMDA receptor are suspected to underlie anti-NMDA receptor encephalitis. Kreye et al. provide direct evidence by showing that monoclonal human NR1 antibodies are sufficient to downregulate synaptic NMDA receptors. They show too that patients harbour a much broader auto-antibody repertoire than previously thought.
Article
Objective: To demonstrate that Ephrin-B2 (the ligand of EphB2 receptor) antagonizes the pathogenic effects of patients' N-methyl-D-aspartate receptor (NMDAR) antibodies on memory and synaptic plasticity. Methods: 122 C57BL/6J mice infused with cerebrospinal fluid (CSF) from patients with anti-NMDAR encephalitis or controls, with or without ephrin-B2, were investigated. CSF was infused through ventricular catheters connected to subcutaneous osmotic pumps over 14 days. Memory, behavioral tasks, locomotor activity, presence of human antibodies specifically bound to hippocampal NMDAR, and antibody effects on the density of cell surface and synaptic NMDAR and EphB2 were examined at different time points using reported techniques. Short and long-term synaptic plasticity were determined in acute brain sections; the Schaffer collateral pathway was stimulated and the field excitatory postsynaptic potentials were recorded in the CA1 region of the hippocampus. Results: Mice infused with patients' CSF, but not control CSF, developed progressive memory and depressive-like behavior along with deposits of NMDAR antibodies in the hippocampus. These findings were associated with a decrease of the density of cell-surface and synaptic NMDAR and EphB2, and marked impairment of long-term synaptic plasticity without altering short-term plasticity. The administration of ephrin-B2 prevented the pathogenic effects of the antibodies in all the investigated paradigms, including memory, depressive-like behavior, density of cell-surface and synaptic NMDAR and EphB2, and long-term synaptic plasticity. Interpretation: Administration of ephrin-B2 prevents the pathogenic effects of anti-NMDAR encephalitis antibodies on memory and behavior, levels of cell-surface NMDAR, and synaptic plasticity. These findings reveal a strategy beyond immunotherapy to antagonize patients' antibody effects. This article is protected by copyright. All rights reserved.
Article
Since the early 1990s it has been postulated that hypofunction of N-methyl-d-aspartate (NMDA) receptors in brain networks supporting perception and cognition underlies schizophrenic psychosis. Recently, NMDA receptor hypofunction was described in patients with psychotic manifestations who exhibited autoantibodies binding the GluN1 subunit of the receptor, and who improved when the level of these antibodies was lowered by immunomodulation. In this disorder, NMDA receptor antibodies decrease the availability of NMDA receptors by internalizing them. In this opinion article, we review this mechanism as well as data supporting or refuting the possibility that this disorder or similar autoimmune disorders affecting synaptic proteins, which are therefore treatable with immunomodulation, could account for some cases of idiopathic psychosis. We also suggest methodological approaches to clarify this issue.
Chapter
Schizophrenia is a severe mental illness that affects almost 1% of the population worldwide. Even though the etiology of schizophrenia is uncertain, it is believed to be a neurodevelopmental disorder that results from a combination of environmental insults and genetic vulnerabilities. Over the past 20 years, there has been a confluence of evidence from many research disciplines pointing to alterations in excitatory signaling, particularly involving hypofunction of the N-methyl-d-aspartate receptor (NMDAR), as a key contributor to the schizophrenia disease process. This review describes the structure–function relationship of the NMDAR channel and how the glycine modulatory site acts as an important regulator of its activity. In addition, this review highlights the genetic, pharmacologic, and biochemical evidence supporting the hypothesis that NMDAR hypofunction contributes to the pathophysiology of schizophrenia. Finally, this chapter highlights some of the most recent and promising pharmacological strategies that are designed to either, directly or indirectly, augment NMDAR function in an effort to treat the cognitive and negative symptoms of schizophrenia that are not helped by currently available medications.
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Autoantibodies targeting proteins at the neuromuscular junction are known to cause several distinct myasthenic syndromes. Recently, autoantibodies targeting neurotransmitter receptors and associated proteins have also emerged as a cause of severe, but potentially treatable, diseases of the CNS. Here, we review the clinical evidence as well as in vitro and in vivo experimental evidence that autoantibodies account for myasthenic syndromes and autoimmune disorders of the CNS by disrupting the functional or structural integrity of synapses. Studying neurological and psychiatric diseases of autoimmune origin may provide new insights into the cellular and circuit mechanisms underlying a broad range of CNS disorders.
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Autoimmune encephalitis is increasingly recognized in patients with otherwise unexplained encephalopathy with epilepsy. Among these, patients with anti-N-methyl D-aspartate receptor (NMDAR) encephalitis present epileptic seizures, memory deficits, and psychiatric symptoms. However, the functional consequences of such autoantibodies are poorly understood. In order to investigate the pathophysiology of this disease, we stereotactically injected either cerebrospinal fluid (CSF) from three anti-NMDAR encephalitis patients or commercially available anti-NMDAR1 into the dentate gyrus of adult female rats. Control animals were injected with either CSF obtained from three epilepsy patients (ganglioglioma, posttraumatic epilepsy, focal cortical dysplasia) lacking anti-NMDAR or saline. Intracellular recordings from dentate gyrus granule cells showed a significant reduction of the NMDAR-evoked excitatory postsynaptic potentials (NMDAR-EPSPs) in animals treated with anti-NMDAR. As a consequence of this, action potential firing in these cells by NMDAR-EPSPs was significantly impaired. Long-term potentiation in the dentate gyrus was also significantly reduced in rats injected with anti-NMDAR as compared to control animals. This was accompanied by a significantly impaired learning performance in the Morris water maze hidden platform task when the animals had been injected with anti-NMDAR antibody-containing CSF. Our findings suggest that anti-NMDAR lead to reduced NMDAR function in vivo which could contribute to the memory impairment found in patients with anti-NMDAR encephalitis.
Article
The immune system has been implicated in the etiology of schizophrenia. Autoimmunity by antibodies against neuronal cell surface antigens has been proposed as one of the pathological mechanisms. We examined plasma samples of 104 patients diagnosed with schizophrenia for the presence of autoantibodies against neuronal cell surface antigens using cultured hippocampal neurons and transfected HeLa cells. None of the samples tested positive for the presence of these autoantibodies. Based on our results it seems unlikely that autoantibodies against neuronal cell surface antigens play a role in the pathogenesis of schizophrenia, although further studies using cerebrospinal fluid are needed.
Article
Identifying the underlying cellular mechanisms of episodic memory is an important challenge, since this memory, based on temporal and contextual associations among events, undergoes preferential degradation in aging and various neuropsychiatric disorders. Memory storage of temporal and contextual associations is known to rely on hippocampal N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity, which depends ex vivo on dynamic organization of surface NMDARs. Whether NMDAR surface trafficking sustains the formation of associative memory, however, remains unknown. We tested this hypothesis, using single nanoparticle imaging, electrophysiology, and behavioral approaches, in hippocampal networks challenged with a potent modulator of NMDAR-dependent synaptic plasticity and memory, 17β-estradiol (E2). We demonstrate that E2 modulates NMDAR surface trafficking, a necessary condition for E2-induced potentiation at hippocampal cornu ammonis 1 synapses. Strikingly, cornu ammonis 1 NMDAR surface trafficking controls basal and E2-enhanced mnemonic retention of temporal, but not contextual, associations. NMDAR surface trafficking and its modulation by the sex hormone E2 is a cellular mechanism critical for a major component of episodic memory, opening a new and noncanonical research avenue in the physiopathology of cognition. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
Article
In recent years, autoantibodies to proteins or receptors expressed on the surface of neurons have been detected in movement and psychiatric disorders. These autoantibodies can assist in better recognition of clinical syndromes and offer novel treatment opportunities via immunotherapies, potentially leading to improved patient outcome. In this review, we describe several autoimmune syndromes associated with movement and psychiatric disorders, including anti-N-methyl-d-aspartate receptor encephalitis, basal ganglia encephalitis, Sydenham chorea, and autoantibody-associated psychosis and schizophrenia. However, rather than focusing on clinical aspects of these diseases, as they have been reviewed in detail elsewhere, we mainly focus on the scientific aspects of the different methodologies for detecting antibodies, with an emphasis on the current gold standard in the field, the cell-based assay, and on issues related to the use of live versus permeabilized cells. We also reflect on the implications associated with the choice of patient serum and cerebrospinal fluid for antibody testing, on the mechanism of antibody entry into the central nervous system through the blood-brain barrier, and the essential issue of antibody pathogenicity. © 2015 New York Academy of Sciences.
Article
The term anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis refers to an autoimmune disorder in which IgG antibodies (ABs) against the NR1 subunit of NMDAR cause receptor internalization and decreased NMDAR-mediated neurotransmission. NMDAR encephalitis predominantly affects women, children and young adults, occurs with or without tumor association and is characterized by a predictable set of symptoms including psychosis as a common early feature, disorganized behavior, motor (e.g. catatonia and dyskinesia) manifestations and seizures.
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Significance A pulse of the adrenal hormone corticosterone (CORT) changes hippocampal glutamate transmission for many hours. CORT is normally released in hourly pulses, with a steeply rising amplitude just before awakening. How organisms can be prepared for imminent danger if the first high-amplitude pulse of CORT would lastingly change glutamate transmission—thus potentially deadlocking the system—has remained an enigma. We show that exposure of hippocampal cells to a second high-amplitude CORT pulse completely normalizes all aspects of glutamate transmission (including synaptic plasticity), thus lifting the potential deadlock caused by a first pulse. This ensures that the system remains fully responsive to any stressful event that requires encoding of information, an important principle that promotes survival of individuals.
Article
Background The dopamine and glutamate hypotheses are well known in psychosis. Recently, the detection of autoantibodies against proteins expressed on the surface of cells in the central nervous system has raised the possibility that specific immune-mediated mechanisms may define a biological subgroup within psychosis, although no cohort of a first episode of psychosis in children have been investigated. Methods Serum taken during the acute presentation of 43 children with first episode of psychosis and serum from 43 pediatric controls was assessed for the presence of IgG, IgM, or IgA antibodies to dopamine-2 receptor (D2R) and NR1 subunit of the N-methyl-D-aspartate receptor (NMDAR) using a flow cytometry live cell-based assay, and immunolabelling of murine primary neurons. Results Using a cut-off of 3SD above the control mean, serum antibodies to D2R or NR1 were detected in 8/43 psychotic patients, but not detected in any of 43 control patients (P < 0.001). Positive immunoglobulin binding to D2R was found in 3/43 psychosis patients (3 IgG, 1 IgM, 0 IgA) and to NMDAR in 6/43 patients (5 IgG, 1 IgM, 1 IgA). Specificity of antibody was confirmed by immunoaffinity purification and immunoabsorption. Significant differences in antibody binding to live, fixed, and fixed and permeabilised neurons were observed, confirming that only live cells can define surface epitope immunolabelling. Conclusions This is the first report of serum antibodies to surface D2R and NR1 in paediatric patients with isolated psychosis, which supports the hypothesis that a subgroup of patients may be immune-mediated.