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

被引：134

作者：

Labrie, Viviane ^{[1
,2
]}

Fukumura, Ryutaro ^{[5
]}

Rastogi, Anjali ^{[3
]}

Fick, Laura J. ^{[4
]}

Wang, Wei ^{[6
]}

Boutros, Paul C. ^{[8
]}

Kennedy, James L. ^{[9
]}

Semeralul, Mawahib O. ^{[9
]}

Lee, Frankie H. ^{[3
]}

Baker, Glen B. ^{[10
,11
]}

Belsham, Denise D. ^{[4
]}

Barger, Steven W. ^{[7
]}

Gondo, Yoichi ^{[5
]}

Wong, Albert H. C. ^{[9
]}

Roder, John C. ^{[1
,2
]}

机构：

[1] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada

[2] Univ Toronto, Inst Med Sci, Toronto, ON M5S 1A8, Canada

[3] Univ Toronto, Dept Pharmacol, Toronto, ON M5S 1A8, Canada

[4] Univ Toronto, Dept Physiol, Toronto, ON M5S 1A8, Canada

[5] RIKEN BioResource Ctr, Mutagenesis & Genom Team, Tsukuba, Ibaraki 3050074, Japan

[6] Univ Arkansas Med Sci, Dept Neurobiol & Dev Sci, Little Rock, AR 72205 USA

[7] Univ Arkansas Med Sci, Dept Geriatr, Little Rock, AR 72205 USA

[8] MaRS Ctr, Ontario Inst Canc Res, Toronto, ON M5G 0A3, Canada

[9] Ctr Addict & Mental Hlth, Div Neurosci, Toronto, ON M5T 1R8, Canada

[10] Univ Alberta, Dept Psychiat, Neurochem Res Unit, Edmonton, AB T6G 2G3, Canada

[11] Univ Alberta, Dept Psychiat, Bebensee Schizophrenia Res Unit, Edmonton, AB T6G 2G3, Canada

来源：

HUMAN MOLECULAR GENETICS | 2009年 / 18卷 / 17期

基金：

加拿大健康研究院; 加拿大自然科学与工程研究理事会; 美国国家卫生研究院;

关键词：

AMINO-ACID OXIDASE; METHYL-D-ASPARTATE; PRIMARY NEGATIVE SYMPTOMS; NMDA RECEPTORS; MESSENGER-RNA; GENE-EXPRESSION; MAMMALIAN BRAIN; MUTANT MICE; RAT-BRAIN; IGF-II;

D O I：

10.1093/hmg/ddp261

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：3227 / 3243

页数：17

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