RRC ID 11779
Author Labrie V, Fukumura R, Rastogi A, Fick LJ, Wang W, Boutros PC, Kennedy JL, Semeralul MO, Lee FH, Baker GB, Belsham DD, Barger SW, Gondo Y, Wong AH, Roder JC.
Title Serine racemase is associated with schizophrenia susceptibility in humans and in a mouse model.
Journal Hum Mol Genet
Abstract 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.
Volume 18(17)
Pages 3227-43
Published 2009-9-1
DOI 10.1093/hmg/ddp261
PII ddp261
PMID 19483194
PMC PMC2722985
MeSH Animals Case-Control Studies Disease Models, Animal Disease Susceptibility* Female Humans Male Mice Mice, Inbred Strains Mutation Pedigree Racemases and Epimerases / genetics Racemases and Epimerases / metabolism* Schizophrenia / enzymology* Schizophrenia / genetics Schizophrenia / physiopathology Serine / metabolism
IF 5.101
Times Cited 115
WOS Category BIOCHEMISTRY & MOLECULAR BIOLOGY GENETICS & HEREDITY
Resource
Mice RBRCGD000099