Suppression of synaptic plasticity by cerebrospinal fluid from anti-NMDA receptor encephalitis patients

ArticleinNeurobiology of Disease 45(1):610-5 · January 2012with26 Reads
Impact Factor: 5.08 · DOI: 10.1016/j.nbd.2011.09.019 · Source: PubMed
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.

    • "...specifically suppressed LTP (memory formation) in the CA1 area of mouse hippocampus slices (Zhang et al. 2012), our results suggest that the antibodies against NMDARs in CSF from the patients with anti-NMDAR e..."
      Planagumà et al. (2015) showed that brain-bound IgG extracted from the mice treated with NMDAR-CSF could bind to the NMDARs. Taken together with our previous study showing that anti-NMDAR antibodies in patients' CSF specifically suppressed LTP (memory formation) in the CA1 area of mouse hippocampus slices (Zhang et al. 2012), our results suggest that the antibodies against NMDARs in CSF from the patients with anti-NMDAR encephalitis are directly related to the memory disturbance in this form of encephalitis. In conclusion, we have shown that the CSF of patients who are positive for anti-NMDAR antibodies affected the memory function of mice, which is also a major symptom in patients with NMDAR encephalitis.
    [Show abstract] [Hide abstract] ABSTRACT: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is now widely recognized and the patients with this disease show prominent psychiatric symptoms followed by seizures, respiratory failure, involuntary movement, autonomic instability, and amnesia. The anti-NMDAR antibody titer coincides with disease activity, and antibody-deprivation treatment ameliorates neurological symptoms. Previous studies have shown that clusters of NMDARs on the neuronal surface decrease in density upon incubation with the cerebrospinal fluid from patients (NMDAR-CSF), and that the induction of long-term potentiation, a cellular mechanism underlie learning and memory processes, was suppressed with NMDAR-CSF. In this study, we exposed mice to NMDAR-CSF in an attempt to reproduce the human symptoms in mice. CSF was continuously administered via a cannula placed in the lateral ventricle of the mouse that connected to an osmotic pump transplanted in the back of the mouse. From day 8-18, we evaluated the behavior of the mice using standardized tests that were performed serially. Mice exposed to NMDAR-CSF showed impaired spatial memory, as detected with the Morris water maze test. Brain tissue from mice with memory disturbances had decreased content of NMDAR protein in the hippocampal area shown by immunohistochemistry, which is consistent with the anti-NMDAR antibodies affect the expression and function of NMDARs, resulting in anti-NMDAR encephalitis-like symptoms. Also, the mice treated with the NMDAR-CSF did not show inflammatory cell infiltration or neuron loss in their brain tissue and this lack of nervous tissue destruction is encouraging as it is consistent with the idea that this disease can be treated through immunotherapy.
    Preview · Article · Nov 2015 · The Tohoku Journal of Experimental Medicine
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    • "...ody encephalitis suppressed induction of long-term potentiation (LTP) in mouse hippocampal slices [150], suggesting that these antibodies can act as an NMDAR antagonist and thus may be involved in amnesi..."
      Anti- NMDAR antibodies do not activate complement, but decrease the NMDA receptor density by cross-linking and subsequent internalisation, leading to a state of reversible NMDAR hypofunction [91, 110]. Further studies with CSF from patients with anti-NMDAR antibody encephalitis suppressed induction of long-term potentiation (LTP) in mouse hippocampal slices [150], suggesting that these antibodies can act as an NMDAR antagonist and thus may be involved in amnesia. However, there is yet no evidence for complement-mediated or cytotoxic T-cell-mediated neuronal cell death in this disease.
    [Show abstract] [Hide abstract] ABSTRACT: Epilepsy is the tendency to have unprovoked epileptic seizures. Anything causing structural or functional derangement of brain physiology may lead to seizures, and different conditions may express themselves solely by recurrent seizures and thus be labelled "epilepsy." Worldwide, epilepsy is the most common serious neurological condition. The range of risk factors for the development of epilepsy varies with age and geographic location. Congenital, developmental and genetic conditions are mostly associated with the development of epilepsy in childhood, adolescence and early adulthood. Head trauma, infections of the central nervous system (CNS) and tumours may occur at any age and may lead to the development of epilepsy. Infections of the CNS are a major risk factor for epilepsy. The reported risk of unprovoked seizures in population-based cohorts of survivors of CNS infections from developed countries is between 6.8 and 8.3 %, and is much higher in resource-poor countries. In this review, the various viral, bacterial, fungal and parasitic infectious diseases of the CNS which result in seizures and epilepsy are discussed. The pathogenesis of epilepsy due to brain infections, as well as the role of experimental models to study mechanisms of epileptogenesis induced by infectious agents, is reviewed. The sterile (non-infectious) inflammatory response that occurs following brain insults is also discussed, as well as its overlap with inflammation due to infections, and the potential role in epileptogenesis. Furthermore, autoimmune encephalitis as a cause of seizures is reviewed. Potential strategies to prevent epilepsy resulting from brain infections and non-infectious inflammation are also considered.
    Full-text · Article · Oct 2015 · Acta Neuropathologica
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    • "... have a high titer of an anti-NMDAR antibody (×16,000), using a method previously reported (Zhang et al. 2012 ). (B) Control human IgG. ..."
      (A) Patient's IgG. The patient was a 33-year-old woman who showed psychosis, involuntary movements, convulsions and hypoventilation, and was proven to have a high titer of an anti-NMDAR antibody (×16,000), using a method previously reported (Zhang et al. 2012 ). (B) Control human IgG.
    [Show abstract] [Hide abstract] ABSTRACT: Autoimmune synaptic encephalitis is characterized by the presence of autoantibodies against synaptic constituent receptors and manifests as neurological and psychiatric disorders. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is such an autoimmune disorder that predominantly affects young women. It is associated with antibodies against the extracellular region of the NR1 subunit of postsynaptic NMDAR. Each NMDAR functions as a heterotetrameric complex that is composed of four subunits, including NR1 and NR2A, NR2B, or NR2C. Importantly, ovarian teratoma is a typical complication of anti-NMDAR encephalitis in female patients and may contain antigenic neural tissue; however, antigenic sites remain unknown in female patients without ovarian teratoma. The purpose of this study was to investigate the expression of NMDARs in the ovum. We detected NR1 and NR2B immunoreactivity in protein fractions extracted from the bovine ovary and ova by SDS-polyacrylamide gel electrophoresis and immunoblotting analysis. Immunoprecipitates digested with trypsin were analyzed by reverse phase liquid chromatography coupled to tandem mass spectrometry. We obtained the following five peptides: SPFGRFK and KNLQDR, which are consistent with partial sequences of human NR1, and GVEDALVSLK, QPTVAGAPK, and NEVMSSK, which correspond to those of NR2A, NR2B and NR2C, respectively. Immunocytochemical analysis revealed that the bovine ovum was stained with the immunoglobulin G purified from the serum of a patient with anti-NMDAR encephalitis. Taken together, we propose that the normal ovum expresses NMDARs that have strong affinity for the disease-specific IgG. The presence of NMDARs in ova may help explain why young females without ovarian teratomas are also affected by anti-NMDAR encephalitis.
    Preview · Article · Mar 2015 · The Tohoku Journal of Experimental Medicine
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