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

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 endothel...

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Bibliographic Details
Published in:Translational psychiatry 2017-08, Vol.7 (8), p.e1186-e1186
Main Authors: 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 V, Severance, E G
Format: Article
Language:English
Subjects:
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Adult
Animals
Autoantibodies - immunology
Autoimmunity
Behavioral Sciences
Biological Psychology
Cognitive ability
Female
Humans
Male
Medicine
Medicine & Public Health
Mice
Middle Aged
Neurosciences
Original
original-article
Pharmacotherapy
Protozoa
Psychiatry
Receptors, N-Methyl-D-Aspartate - immunology
Rodents
Schizophrenia
Schizophrenia - immunology
Toxoplasma - immunology
Young Adult
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Summary: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.
ISSN:2158-3188
2158-3188
DOI:10.1038/tp.2017.162