Autoimmunity to membrane proteins in the central nervous system has been increasingly recognized as a cause of neuropsychiatric disease. A key recent development was the discovery of autoantibodies to N-methyl-d-aspartate (NMDA) receptors in some cases of encephalitis, characterized by cognitive changes, memory loss, and seizures that could lead to long-term morbidity or mortality. Treatment approaches and experimental studies have largely focused on the pathogenic role of these autoantibodies. Passive antibody transfer to mice has provided useful insights but does not produce the full spectrum of the human disease. Here, we describe a de novo autoimmune mouse model of anti-NMDA receptor encephalitis. Active immunization of immunocompetent mice with conformationally stabilized, native-like NMDA receptors induced a fulminant encephalitis, consistent with the behavioral and pathologic characteristics of human cases. Our results provide evidence for neuroinflammation and immune cell infiltration as components of the autoimmune response in mice. Use of transgenic mice indicated that mature T cells and antibody-producing cells were required for disease induction. This active immunization model may provide insights into disease induction and a platform for testing therapeutic approaches.
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