Suppression of synaptic plasticity by cerebrospinal fluid from anti-NMDA receptor encephalitis patients
ABSTRACT The functional effects of cerebrospinal fluid (CSF) from patients with anti-NMDA receptor (NMDAR) encephalitis on the NMDAR-mediated synaptic plasticity were evaluated by using mouse hippocampus slices. Anti-NMDAR antibody detection system was established by immunostaining recombinant NMDAR heteromers expressed in HEK cell culture as well as native NMDARs in cultured hippocampal neurons. Under a complete blind manner for the clinical information, CSF and sera collected from 36 pre-diagnosed patients were tested for anti-NMDAR antibodies. With this test, thirteen patients were diagnosed as anti-NMDAR encephalitis. CSF positive for anti-NMDAR antibodies suppressed induction of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses in mouse hippocampal slices. LTP induction was not suppressed by CSF collected from herpes simplex virus (HSV) encephalitis or non-encephalitis control patients. Antibody absorption with NMDAR-expressing HEK cell culture reversed the suppression of LTP by anti-NMDAR encephalitis patients' CSF, confirming that anti-NMDAR antibodies suppressed LTP. The present experiments firmly support the proposal that the anti-NMDAR encephalitis autoantibody is responsible for cognitive disorders like amnesia accompanying this disease.
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ABSTRACT: Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is an autoimmune condition caused by immunoglobulin (Ig)G antibodies directed against the NR1 subunit of the NMDA glutamate receptor. Approximately 65% of cases present with psychiatric symptoms, particularly psychosis. It remains to be established whether anti-NMDA receptor antibodies can cause a 'purely' psychotic illness without overt neurological symptoms. We conducted a systematic literature search to establish what proportion of patients with schizophrenia and related psychoses have antibodies directed against the NMDA receptor. Studies were included if (a) subjects had a diagnosis of schizophrenia, schizophrenia spectrum disorder or first-episode psychosis (FEP) using standard criteria, (b) serum was analysed for the presence of anti-NMDA receptor antibodies; and (c) the purpose of the study was to look for the presence of anti-NMDA receptor antibodies in patients with a primary psychiatric diagnosis without clinical signs of encephalitis. Seven studies were included, comprising 1441 patients, of whom 115 [7.98%, 95% confidence interval (CI) 6.69-9.50] were anti-NMDA receptor antibody positive. Of these, 21 (1.46%, 95% CI 0.94-2.23) patients were positive for antibodies of the IgG subclass. Prevalence rates were greater in cases than controls only for IgG antibodies; other subclasses are of less certain aetiological relevance. There was significant heterogeneity in terms of patient characteristics and the antibody assay used. A minority of patients with psychosis are anti-NMDA receptor antibody positive. It remains to be established whether this subset of patients differs from antibody-negative patients in terms of underlying pathology and response to antipsychotic treatment, and whether immunomodulatory treatments are effective in alleviating psychotic symptoms in this group.Psychological Medicine 12/2013; DOI:10.1017/S003329171300295X · 5.43 Impact Factor
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ABSTRACT: Autoimmune synaptic encephalitides are recently described human brain diseases leading to psychiatric and neurological syndromes through inappropriate brain-autoantibody interactions. The most frequent synaptic autoimmune encephalitis is associated with autoantibodies against extracellular domains of the glutamatergic N-methyl-d-aspartate receptor, with patients developing psychotic and neurological symptoms in an autoantibody titre-dependent manner. Although N-methyl-d-aspartate receptors are the primary target of these antibodies, the cellular and molecular pathway(s) that rapidly lead to N-methyl-d-aspartate receptor dysfunction remain poorly understood. In this report, we used a unique combination of high-resolution nanoparticle and bulk live imaging approaches to demonstrate that anti-N-methyl-d-aspartate receptor autoantibodies from patients with encephalitis strongly alter, in a time-dependent manner, the surface content and trafficking of GluN2-NMDA receptor subtypes. Autoantibodies laterally displaced surface GluN2A-NMDA receptors out of synapses and completely blocked synaptic plasticity. This loss of extrasynaptic and synaptic N-methyl-d-aspartate receptor is prevented both in vitro and in vivo, by the activation of EPHB2 receptors. Indeed, the anti-N-methyl-d-aspartate receptor autoantibodies weaken the interaction between the extracellular domains of the N-methyl-d-aspartate and Ephrin-B2 receptors. Together, we demonstrate that the anti-N-methyl-d-aspartate receptor autoantibodies from patients with encephalitis alter the dynamic retention of synaptic N-methyl-d-aspartate receptor through extracellular domain-dependent mechanism(s), shedding new light on the pathology of the neurological and psychiatric disorders observed in these patients and opening possible new therapeutic strategies.Brain 05/2012; 135(Pt 5):1606-21. DOI:10.1093/brain/aws092 · 10.23 Impact Factor
- European Journal of Neurology 11/2011; 18(11):e145-6. DOI:10.1111/j.1468-1331.2011.03485.x · 3.85 Impact Factor