We propose to characterize the autoimmune responses to neuronal cell surface and synaptic proteins that result in catatonia, autistic behaviors and other neuropsychiatric disturbances. In 2007, we reported a group of young women who acutely developed psychotic behavior or schizophrenia-like symptoms, subsequently followed by memory defects, catatonia, abnormal movements, and autonomic dysfunction. Using a set of techniques that we optimized, we found that all patients had antibodies against the NR1 subunit of the N- methyl-D-aspartate receptor (NMDAR), a glutamate receptor involved in synaptic transmission and plasticity. In about 60% of these patients, the trigger of the immune response was an ovarian teratoma that contained ectopic nervous tissue expressing NMDAR. Since that report, the number of patients with this disorder has rapidly increased, and similar clinical and laboratory strategies applied to patients with other neuropsychiatric disorders have resulted in the discovery of 6 novel immune responses to cell surface/synaptic autoantigens, including among others the GluR1/2 subunits of the AMPA receptor (AMPAR), the GABA(B1) receptor (GABA(B1)R), Leucine rich glioma inactivated 1 (LGI1) and Contactin associated protein 2 (Caspr2). This work is significant because: 1) the disorders affect young adults, including men and children with or without tumors;2) they are responsive to immunotherapy;3) some antibodies define new syndromes;4) the characterization of the antigens has resulted in unambiguous diagnostic tests;and 5) patient antibodies have titer dependent and reversible effects on the function of the target receptors / proteins. Overall, these findings have led to the hypothesis that many subacute psychiatric disorders of unknown etiology, including catatonia or autistic behaviors, either alone or in association with other neurologic manifestations, are likely mediated by antibodies that affect neurotransmitter receptors at cell surface or synaptic sites. We will test this hypothesis in 3 goals. (1) We will select patients with one of 3 disorders for which we have preliminary evidence of serum or CSF antibodies to cell surface/synaptic proteins: rapidly progressive neuropsychiatric disorders with catatonic features, the spectrum of acquired rapidly progressive autistic behavior in children and adults, and limbic encephalopathy in children and adolescents. (2) We will identify the autoantigens in these 3 disorders, using highly sensitive methods we have developed and optimized to detect neuronal cell surface / synaptic antigens;and (3) We will use in vitro and in vivo studies to determine how patients'antibodies against novel cell surface/synaptic antigens affect neuron and synaptic structure and function, and how these recover after antibodies are removed. We will establish the autoimmune processes that lead to catatonia, autistic features, and limbic encephalopathy and the underlying cellular and synaptic mechanisms. Identification of autoimmune mechanisms will result in improved therapeutic interventions for these disorders in children and adults that will have a significant health impact and reduce the burden of neurological and neuropsychiatric disease.

Public Health Relevance

We propose to screen patients presenting with rapidly progressive neuropsychiatric disorders with catatonic features, the spectrum of acquired rapidly progressive autistic behavior in children and adults, and limbic encephalopathy in children and adolescents, for the presence of autoimmune processes. We hypothesize that these subacute psychiatric disorders of unknown etiology, that occur alone or in association with neurologic manifestations, are likely mediated by antibodies that affect cell surface or synaptic proteins, leading to circuit dysfunction. We will test this hypothesis in these 3 disorders because we have preliminary evidence that patients'serum or cerebrospinal fluid contain antibodies to cell surface/ synaptic proteins. Achieving the goals we propose will provide fundamentally new insights into the role of autoimmune processes in these symptoms and reveal the underlying cellular, synaptic and circuit mechanisms. Our work will likely lead to novel avenues for therapeutic intervention in these neuropsychiatric disorders that have a significant public health impact.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZNS1-SRB-B (26))
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Meinecke, Douglas L
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University of Pennsylvania
Schools of Medicine
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Masdeu, Joseph C; Dalmau, Josep; Berman, Karen F (2016) NMDA Receptor Internalization by Autoantibodies: A Reversible Mechanism Underlying Psychosis? Trends Neurosci :
Gövert, Felix; Witt, Karsten; Erro, Roberto et al. (2016) Orthostatic myoclonus associated with Caspr2 antibodies. Neurology 86:1353-5
Guasp, Mar; Solà-Valls, Nuria; Martínez-Hernández, Eugenia et al. (2016) Cerebellar ataxia and autoantibodies restricted to glutamic acid decarboxylase 67 (GAD67). J Neuroimmunol 300:15-17
Maccaferri, G E; Rossetti, A O; Dalmau, J et al. (2016) Anti-N-Methyl-D-Aspartate Receptor Encephalitis: A New Challenging Entity for Consultation-Liaison Psychiatrist. Brain Disord Ther 5:
Kayser, Matthew S; Dalmau, Josep (2016) Anti-NMDA receptor encephalitis, autoimmunity, and psychosis. Schizophr Res 176:36-40
Leypoldt, Frank; Armangue, Thaís; Dalmau, Josep (2015) Autoimmune encephalopathies. Ann N Y Acad Sci 1338:94-114
Gresa-Arribas, Nuria; Ariño, Helena; Martínez-Hernández, Eugenia et al. (2015) Antibodies to inhibitory synaptic proteins in neurological syndromes associated with glutamic acid decarboxylase autoimmunity. PLoS One 10:e0121364
Höftberger, Romana; van Sonderen, Agnes; Leypoldt, Frank et al. (2015) Encephalitis and AMPA receptor antibodies: Novel findings in a case series of 22 patients. Neurology 84:2403-12
Armangue, Thaís; Santamaria, Joan; Dalmau, Josep (2015) When a serum test overrides the clinical assessment. Neurology 84:1379-81
Ariño, Helena; Höftberger, Romana; Gresa-Arribas, Nuria et al. (2015) Paraneoplastic Neurological Syndromes and Glutamic Acid Decarboxylase Antibodies. JAMA Neurol 72:874-81

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