期刊
BIOLOGICAL PSYCHIATRY
卷 82, 期 10, 页码 756-765出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2016.12.011
关键词
Anxiety; Cognition; Kynurenic acid; Locomotor activity; Schizophrenia; Social interaction
资金
- AstraZeneca
- Swedish Medical Research Council [2009-7053, 2013-2838]
- Swedish Brain Foundation
- Torsten Sderbergs Stiftelse
- Parkinson's UK
- Biotechnology and Biological Sciences Research Council
- AstraZeneca-Karolinska Institutet Joint Research Program in Translational Science
- Higher Education Innovation Fund
- U.S. Public Health Service [P50 MH103222, K12 HD43489-14]
- MRC [MR/N00373X/1] Funding Source: UKRI
- Medical Research Council [MR/N00373X/1] Funding Source: researchfish
- Parkinson's UK [G-0902] Funding Source: researchfish
BACKGROUND: Kynurenine 3-monooxygenase converts kynurenine to 3-hydroxykynurenine, and its inhibition shunts the kynurenine pathway-which is implicated as dysfunctional in various psychiatric disorders-toward enhanced synthesis of kynurenic acid, an antagonist of both alpha 7 nicotinic acetylcholine and N-methyl-D-aspartate receptors. Possibly as a result of reduced kynurenine 3-monooxygenase activity, elevated central nervous system levels of kynurenic acid have been found in patients with psychotic disorders, including schizophrenia. METHODS: In the present study, we investigated adaptive-and possibly regulatory-changes in mice with a targeted deletion of Kmo (Kmo(-/-)) and characterized the kynurenine 3-monooxygenase-deficient mice using six behavioral assays relevant for the study of schizophrenia. RESULTS: Genome-wide differential gene expression analyses in the cerebral cortex and cerebellum of these mice identified a network of schizophrenia-and psychosis-related genes, with more pronounced alterations in cerebellar tissue. Kynurenic acid levels were also increased in these brain regions in Kmo(-/-) mice, with significantly higher levels in the cerebellum than in the cerebrum. Kmo(-/-) mice exhibited impairments in contextual memory and spent less time than did controls interacting with an unfamiliar mouse in a social interaction paradigm. The mutant animals displayed increased anxiety-like behavior in the elevated plus maze and in a light/dark box. After a D-amphetamine challenge (5 mg/kg, intraperitoneal), Kmo(-/-) mice showed potentiated horizontal activity in the open field paradigm. CONCLUSIONS: Taken together, these results demonstrate that the elimination of Kmo in mice is associated with multiple gene and functional alterations that appear to duplicate aspects of the psychopathology of several neuropsychiatric disorders.
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