Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction

Darrick T. Balu1,2, Yan Li1, Matthew D. Puhl1,2, Michael A. Benneyworth1,2, Alo C. Basu1,2, Shunsuke Takagi3, Vadim Y. Bolshakov1, Joseph T. Coyle1,2
1Department of Psychiatry, Harvard Medical School, Boston, MA 02115
2Laboratory for Psychiatric and Molecular Neuroscience, Department of Psychiatry, McLean Hospital, Belmont, MA 02478; and
3Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan

Tóm tắt

SignificanceWe sought to determine whether the diverse hippocampal neuropathology observed in schizophrenia could be recapitulated in an animal model of NMDA receptor (NMDAR) hypofunction. Serine racemase-deficient (SR−/−) mice, which lack one of the NMDAR coagonistsd-serine, display impaired hippocampal plasticity, as well as the morphological, neurochemical, and cognitive abnormalities consistent with what is observed in schizophrenia. Importantly, treatment in adulthood withd-serine reversed the electrophysiological, neurochemical, and cognitive deficits. These results demonstrate that NMDAR hypofunction can reproduce the hippocampal deficits associated with schizophrenia and point to potential interventions for the currently untreatable negative and cognitive symptoms of this disorder.

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