Mechanisms by which NMDA receptor antibodies mediate a novel autoimmune disease

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DESCRIPTION (provided by applicant): Neural paraneoplastic syndromes arise when an immune response to a tumor cross reacts with a protein in the nervous system, causing alterations of neuronal function. Recently, our laboratory in collaboration with the laboratory of Dr. Josep Dalmau (Department of Neurology, Hospital of the University of Pennsylvania) has helped characterize a new paraneoplastic syndrome, anti-N-methyl-D-aspartate receptor (a-NMDAR) encephalitis. This syndrome develops in patients with teratomas that express NMDARs, who then present with a variety of neurological problems including amnesia, psychosis, and autonomic distress. We have found over 40 patients in 3 years, indicating that this disorder frequently goes undiagnosed and untreated, probably resulting in death from autonomic instability. Patients recover with plasmapheresis, indicating antibody involvement. While we have previously shown that these patients make a-NMDA receptor antibodies, it is unclear how these antibodies mediate this phenotype. NMDAR hypofunction has previously been implicated in the pathogenesis of schizophrenia; based on the similarities of the clinical phenomena, it is possible that a-NMDAR encephalitis represents an autoimmune disorder that mimics the neurological changes occurring in schizophrenia. I propose to investigate the mechanisms by which NMDAR antibodies trigger these neurological problems, which may provide broader insights into the general mechanisms of schizophrenia. To do so, I will use whole-cell patch clamp and Ca2+ imaging to determine if these antibodies have a direct effect on channel function. These antibodies could also change in the number of channels on the cell surface or the location of those channels, possibly by disrupting an interaction with an anchoring protein. I will examine this possibility with cell-surface labeling techniques, primarily biotinylations. Finally, I will map the main immunogen of the receptor by transfecting HEK293 cells with mutant NMDAR subunits that are missing portions of the receptor, as well as chimeric receptors. Finding the epitope could help develop an immunodiagnostic test, preventing unnecessary deaths. PUBLIC HEALTH RELEVANCE: One of the major theories of the cause of schizophrenia is hypofunction of the NMDA receptor. Anti-NMDAR encephalitis, therefore, in which individuals make antibodies to the NMDAR that then cause psychological symptoms similar to schizophrenia, presents a unique opportunity for studying the specific contribution of this receptor. In addition to this possible mechanistic connection to schizophrenia, however, this disease was only recently discovered and seems to frequently go undiagnosed and therefore untreated. Developing a better test for this condition, which this research could help do, would help solve this problem.