title: Serine racemase is associated with schizophrenia susceptibility in humans and in a mouse model.
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.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. abrie@lunenfeld.ca
authors.forename: Viviane
authors.initials: V
authors.lastname: Labrie
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Fukumura
authors.forename: Anjali
authors.initials: A
authors.lastname: Rastogi
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Fick
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
authors.forename: James L
authors.initials: JL
authors.lastname: Kennedy
authors.forename: Mawahib O
authors.initials: MO
authors.lastname: Semeralul
authors.forename: Frankie H
authors.initials: FH
authors.lastname: Lee
authors.forename: Glen B
authors.initials: GB
authors.lastname: Baker
authors.forename: Denise D
authors.initials: DD
authors.lastname: Belsham
authors.forename: Steven W
authors.initials: SW
authors.lastname: Barger
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Gondo
authors.forename: Albert H C
authors.initials: AH
authors.lastname: Wong
authors.forename: John C
authors.initials: JC
authors.lastname: Roder
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D010375:Pedigree; D019998:Racemases and Epimerases / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D012694:Serine / Q000378:metabolism; D000099300:Serine Racemase
chemical_list: D019998:Racemases and Epimerases; D012694:Serine; D000099300:Serine Racemase