Anti-NMDA receptor autoantibodies in psychotic disorders: Mechanisms of action

The flourishing identification of circulating autoantibodies against neuronal receptors in neuropsychiatric patients has fostered new conceptual and clinical frameworks, constituting today one of the hottest topic in psychiatry. At the same time, their detection in multiple neurological and psychiatric disorders raised questions on their physiopathological mode of action and possible use as biomarkers. Using cutting-edge single molecule and classical imaging approaches, we explored the synaptic impact of purified autoantibodies against glutamate NMDA receptor (NMDAR-Ab) from schizophrenic patients and matched healthy controls. Schematically, we uncovered that NMDAR-Ab from schizophrenic patients are pathogenic at the molecular level, not because they alter the function of the ionotropic receptor but rather because they “displaced” NMDAR. In addition, surface dopamine receptors are also affected by NMDAR-Ab. These new insights generate new conceptual research framework and open perspectives at several levels. Identifying the precise pathological cellular and molecular cascade(s) induced by these autoantibodies will allow designing innovative therapeutical strategies to either prevent the effect of autoantibodies or correct their trafficking alteration on the receptors. Pre-clinical proof-of-concepts and academic-industrial partnership are thus timely in the blooming immune-psychiatry field.