Pathogen-mediated NMDA receptor autoimmunity and cellular barrier dysfunction in schizophrenia

G. Kannan, K. L. Gressitt, S. Yang, C. R. Stallings, E. Katsafanas, L. A. Schweinfurth, C. L.G. Savage, M. B. Adamos, K. M. Sweeney, A. E. Origoni, S. Khushalani, S. Bahn, F. M. Leweke, F. B. Dickerson, Robert H Yolken, Mikhail Pletnikov, Emily G Severance

Research output: Contribution to journalArticle

Abstract

Autoantibodies that bind the N-methyl-D-aspartate receptor (NMDAR) may underlie glutamate receptor hypofunction and related cognitive impairment found in schizophrenia. Exposure to neurotropic pathogens can foster an autoimmune-prone environment and drive systemic inflammation leading to endothelial barrier defects. In mouse model cohorts, we demonstrate that infection with the protozoan parasite, Toxoplasma gondii, caused sustained elevations of IgG class antibodies to the NMDAR in conjunction with compromised blood-gut and blood-brain barriers. In human cohorts, NMDAR IgG and markers of barrier permeability were significantly associated with T. gondii exposure in schizophrenia compared with controls and independently of antipsychotic medication. Combined T. gondii and NMDAR antibody seropositivity in schizophrenia resulted in higher degrees of cognitive impairment as measured by tests of delayed memory. These data underscore the necessity of disentangling the heterogeneous pathophysiology of schizophrenia so that relevant subsets eligible for NMDAR-related treatment can be identified. Our data aid to reconcile conflicting reports regarding a role of pathological NMDAR autoantibodies in this disorder.

Original languageEnglish (US)
Article numbere1186
JournalTranslational Psychiatry
Volume7
Issue number8
DOIs
StatePublished - Aug 1 2017

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health
  • Biological Psychiatry

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    Kannan, G., Gressitt, K. L., Yang, S., Stallings, C. R., Katsafanas, E., Schweinfurth, L. A., Savage, C. L. G., Adamos, M. B., Sweeney, K. M., Origoni, A. E., Khushalani, S., Bahn, S., Leweke, F. M., Dickerson, F. B., Yolken, R. H., Pletnikov, M., & Severance, E. G. (2017). Pathogen-mediated NMDA receptor autoimmunity and cellular barrier dysfunction in schizophrenia. Translational Psychiatry, 7(8), [e1186]. https://doi.org/10.1038/tp.2017.162