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Transl Psychiatry. 2017 Aug 1;7(8):e1186. doi: 10.1038/tp.2017.162.

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

Author information

1
Department of Psychiatry, Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
2
Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
3
Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
4
Sheppard Pratt Health System, Stanley Research Program, Baltimore, MD, USA.
5
Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK.
6
Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
7
Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.
8
Department of Molecular Immunology and Microbiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

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.

PMID:
28763062
PMCID:
PMC5611729
DOI:
10.1038/tp.2017.162
[Indexed for MEDLINE]
Free PMC Article

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