The antipsychotic drug clozapine suppresses autoimmunity driving psychosis-like behavior in mice
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Le He Harriet Feldman Timothy Nguyen Marion Bosc Vasishta Polisetty Orla Kriel Antonia Landwehr Annabel Borg Fernanda Teixeira Subtil Mohammadparsa Khakpour Jitong Zhou Svend Kjaer James MacCabe Thomas A Pollak Marie-Eve Tremblay Carola Vinuesa Adrian Hayday Katharina SchmackThis article is a preprint. Preprints have not been peer-reviewed.
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Abstract
Antipsychotic drugs are the first-line treatment for psychosis yet their mechanism of action remains poorly understood, largely due to the challenge to faithfully model psychosis preclinically. Here, we focus on the emerging concept that psychosis can be caused by brain autoimmunity and present a novel mouse model of anti-N-methyl-D-aspartate-receptor (anti-NMDAR) encephalitis, a condition that manifests with psychosis and autoantibodies against the NMDAR. We devised a new mRNA-based approach to immunize mice against the NMDAR. Immunized mice developed psychosis-like behaviors that were caused by anti-NMDAR autoantibodies leading to phagocytosis of NMDARs by brain micro-glia. The antipsychotic drug clozapine rescued psychosis-like behaviors and, remarkably, reduced anti-NMDAR autoantibody levels and antibody-mediated phagocytosis of NMDARs. The immunomodulato-ry effects of clozapine were confirmed in a mouse model of systemic lupus erythematosus. Our results demonstrate that clozapine suppresses autoimmunity driving psychosis-like behaviors, raising the possibility that immunomodulation contributes to antipsychotic drug action.
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