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Abstract
High titers of anti-NMDAR1 autoantibodies in brain cause anti-NMDAR1 encephalitis that displays psychiatric symptoms of schizophrenia and/or other psychiatric disorders in addition to neurological symptoms. Low titers of anti-NMDAR1 autoantibodies are reported in the blood of a subset of the general human population and psychiatric patients. Since ~0.1-0.2% of blood circulating antibodies cross the blood-brain barriers and antibodies can persist for months and years in human blood, it is important to investigate whether chronic presence of these blood circulating anti-NMDAR1 autoantibodies may impair human cognitive functions and contribute to the development of psychiatric symptoms. Here, we generated mice carrying low titers of anti-NMDAR1 autoantibodies in blood against a single antigenic epitope of mouse NMDAR1. Mice carrying the anti-NMDAR1 autoantibodies are healthy and display no differences in locomotion, sensorimotor gating, and contextual memory compared to controls. Chronic presence of the blood circulating anti-NMDAR1 autoantibodies, however, is sufficient to impair T-maze spontaneous alternation in the integrity of blood-brain barriers across all 3 independent mouse cohorts, indicating a robust cognitive deficit in spatial working memory and/or novelty detection. Our studies implicate that chronic presence of low titers of blood circulating anti-NMDAR1 autoantibodies may impair cognitive functions in both the general healthy human population and psychiatric patients.
Highlights
N-methyl-D-aspartate receptor (NMDAR) in brain is essential for learning and memory as well as other cognitive functions
Anti-NMDAR1 autoantibodies were detectable by IHC 3 weeks after immunization, and 5 out of 9 immunized mice developed the anti-NMDAR1 autoantibodies in blood by week 9 (WK9) (Fig 1C)
Our studies are the first characterization of mice carrying anti-NMDAR1 autoantibodies against a single specific antigenic epitope
Summary
N-methyl-D-aspartate receptor (NMDAR) in brain is essential for learning and memory as well as other cognitive functions. Pharmacological studies demonstrated that NMDAR antagonists cause schizophrenia-like symptoms in human [1]. Recent human genetic studies further validated the central role of NMDAR functions in the development of schizophrenia [2, 3]. In addition to genetic mutations, NMDAR functions can be impaired by physiological/.
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