This application addresses broad Challenge Area (01): Behavior, Behavioral Change, and Prevention and specific Challenge Topic 01-AA-102: Functional Roles of Neuroimmune Factors in Mediating Behavior. The focus of this proposal is the characterization of autoimmune responses to synaptic proteins that result in disorders of behavior, memory, cognition and psychosis. In 2007, we first reported a group of young women who acutely developed psychotic behavior or schizophrenia, subsequently followed by decrease of memory, catatonia, abnormal movements, and autonomic dysfunction. Using techniques that we optimized to detect antibodies to neuronal cell surface and/or synaptic proteins, we found that all patients had antibodies against the NR1 subunit of the NMDA receptor, a glutamate receptor that plays important roles in synaptic transmission and plasticity. In about 60% of patients, the immune trigger was an ovarian teratoma with ectopic nervous tissue and expressed NMDAR. Since that report, the number of patients diagnosed with this disorder has rapidly increased, and similar strategies applied to patients with other neuropsychiatric manifestations have led to the discovery of 4 novel immune responses to cell surface/synaptic autoantigens, including, among others, the GluR1/2 subunits of the AMPA receptor, and the GABA(B1) receptor. Our recently published studies have shown that patients'NMDAR or AMPAR antibodies reduce the number and synaptic localization of receptor clusters in dissociated hippocampal neurons in vitro, and that these effects are reversed upon removal of antibodies from the culture medium. These findings have led to the hypothesis that many acute encephalopathies of unknown etiology causing behavioral, personality and memory deficits are likely mediated by antibodies that affect neurotransmitter receptors at cell surface or synaptic sites. In 3 disorders for which preliminary studies show CSF antibodies to cell surface/synaptic proteins, including rapidly progressive psychosis;acute behavioral deficits, language dysfunction and mutism in children;and acute memory deficits and anterograde amnestic syndromes, we will perform 2 aims: 1) Determine the identity of the autoantigens in these 3 disorders, using modified highly sensitive methods to detect the presence of antibodies to neuronal cell surface/synaptic antigens;and 2) Determine how patients'antibodies modify the structure and function of synapses in rodent neurons in vitro and in vivo, focusing on how the density and synaptic localization of antigens is altered by patients'antibodies, and how these recover after antibodies are removed. The results of these experiments will allow us to begin to determine the range of autoantigens that lead to encephalopathies with associated behavioral manifestations in humans, and to begin to determine the underlying molecular, cellular and synaptic mechanisms in these common and devastating disorders. We propose to screen patients presenting with encephalopathies of unknown etiology that result in personality, behavior and language dysfunction for autoimmune processes. We hypothesize that patient antibodies affect neurotransmitter receptors in the neuronal membrane and at synapses, leading to changes in synaptic and circuit function that in turn lead to behavioral, personality and memory deficits. The results of the proposed experiments will provide fundamentally new insights into the molecular, cellular, synaptic and behavioral mechanisms underlying anti-glutamate receptor encephalopathies, provide new insights into memory and cognitive deficits that are hallmarks of these disorders, and potentially suggest avenues for therapeutic intervention in these common and devastating disorders of memory and cognition that have a significant public health impact.
We propose to screen patients presenting with encephalopathies of unknown etiology that result in personality, behavior and language dysfunction for autoimmune processes. We hypothesize that patient antibodies affect neurotransmitter receptors in the neuronal membrane and at synapses, leading to changes in synaptic and circuit function that in turn lead to behavioral, personality and memory deficits. The results of the proposed experiments will provide fundamentally new insights into the molecular, cellular, synaptic and behavioral mechanisms underlying anti-glutamate receptor encephalopathies, provide new insights into memory and cognitive deficits that are hallmarks of these disorders, and potentially suggest avenues for therapeutic intervention in these common and devastating disorders of memory and cognition that have a significant public health impact.
| Leypoldt, Frank; Armangue, Thaís; Dalmau, Josep (2015) Autoimmune encephalopathies. Ann N Y Acad Sci 1338:94-114 |
| Titulaer, Maarten J; McCracken, Lindsey; Gabilondo, Iñigo et al. (2013) Late-onset anti-NMDA receptor encephalitis. Neurology 81:1058-63 |
| Titulaer, Maarten J; McCracken, Lindsey; Gabilondo, Iñigo et al. (2013) Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 12:157-65 |
| Armangue, Thaís; Titulaer, Maarten J; Málaga, Ignacio et al. (2013) Pediatric anti-N-methyl-D-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients. J Pediatr 162:850-856.e2 |
| Boronat, Anna; Gelfand, Jeffrey M; Gresa-Arribas, Nuria et al. (2013) Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium channels. Ann Neurol 73:120-8 |
| Rosenfeld, Myrna R; Dalmau, Josep (2012) Paraneoplastic Neurologic Disorders: A Brief Overview. Memo 5:197-200 |
| Tanyi, Janos L; Marsh, Evelyn B; Dalmau, Josep et al. (2012) Reversible paraneoplastic encephalitis in three patients with ovarian neoplasms. Acta Obstet Gynecol Scand 91:630-4 |
| Bseikri, Mustafa R; Barton, Jubilee R; Kulhanjian, Julie A et al. (2012) Anti-N-methyl D-aspartate receptor encephalitis mimics viral encephalitis. Pediatr Infect Dis J 31:202-4 |
| Finke, Carsten; Kopp, Ute A; Prüss, Harald et al. (2012) Cognitive deficits following anti-NMDA receptor encephalitis. J Neurol Neurosurg Psychiatry 83:195-8 |
| Leypoldt, Frank; Buchert, Ralph; Kleiter, Ingo et al. (2012) Fluorodeoxyglucose positron emission tomography in anti-N-methyl-D-aspartate receptor encephalitis: distinct pattern of disease. J Neurol Neurosurg Psychiatry 83:681-6 |
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