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Human Molecular Genetics Advance Access originally published online on May 30, 2009
Human Molecular Genetics 2009 18(17):3227-3243; doi:10.1093/hmg/ddp261
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Serine racemase is associated with schizophrenia susceptibility in humans and in a mouse model

Viviane Labrie1,2,*, Ryutaro Fukumura5, Anjali Rastogi3, Laura J. Fick4, Wei Wang6, Paul C. Boutros8, James L. Kennedy9, Mawahib O. Semeralul9, Frankie H. Lee3, Glen B. Baker10, Denise D. Belsham4, Steven W. Barger6,7, Yoichi Gondo5, Albert H.C. Wong9 and John C. Roder1,2

1 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 2 Institute of Medical Science 3 Department of Pharmacology and 4 Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8 5 Mutagenesis and Genomics Team, RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba 305-0074, Japan 6 Department of Neurobiology & Developmental Sciences and 7 Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA 8 Ontario Institute for Cancer Research, MaRS Center, Toronto, Ontario, Canada M5G 0A3 9 Neuroscience Division, Center for Addiction and Mental Health, Toronto, Ontario, Canada M5T 1R8 10 Neurochemical Research Unit and Bebensee Schizophrenia Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada T6G 2G3

* To whom correspondence should be addressed. Tel: +1 1 4165864800/ext. 8543; Fax: +1 1 4165864767; Email: labrie{at}lunenfeld.ca

Received March 26, 2009; Accepted May 28, 2009

Abnormal N-methyl-D-aspartate receptor (NMDAR) function has been implicated in the pathophysiology of schizophrenia. D-serine is an important NMDAR modulator, and to elucidate the role of the D-serine synthesis enzyme serine racemase (Srr) in schizophrenia, we identified and characterized mice with an ENU-induced mutation that results in a complete loss of Srr activity and dramatically reduced D-serine levels. Mutant mice displayed behaviors relevant to schizophrenia, including impairments in prepulse inhibition, sociability and spatial discrimination. Behavioral deficits were exacerbated by an NMDAR antagonist and ameliorated by D-serine or the atypical antipsychotic clozapine. Expression profiling revealed that the Srr mutation influenced several genes that have been linked to schizophrenia and cognitive ability. Transcript levels altered by the Srr mutation were also normalized by D-serine or clozapine treatment. Furthermore, analysis of SRR genetic variants in humans identified a robust association with schizophrenia. This study demonstrates that aberrant Srr function and diminished D-serine may contribute to schizophrenia pathogenesis.


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