期刊
HIPPOCAMPUS
卷 29, 期 2, 页码 73-77出版社
WILEY
DOI: 10.1002/hipo.23040
关键词
consolidation; glutamate; kynurenic acid; neurodevelopment; schizophrenia
资金
- National Institute of Child Health and Human Development [K12 HD43489-14]
- National Institute of Mental Health [P50 MH103222]
- National Institute of Neurological Disorders and Stroke [R01 NS102209]
- USPHS [R01NS102209, K12HD43489-14, P50MH103222]
A combination of genetic and environmental factors contributes to schizophrenia (SZ), a catastrophic psychiatric disorder with a hypothesized neurodevelopmental origin. Increases in the brain levels of the tryptophan metabolite kynurenic acid (KYNA), an endogenous antagonist of alpha 7 nicotinic acetylcholine and NMDA receptors, have been implicated specifically in the cognitive deficits seen in persons with SZ. Here we evaluated this role of KYNA by adding the KYNA precursor kynurenine (100 mg/day) to chow fed to pregnant rat dams from embryonic day (ED) 15 to ED 22 (control: ECon; kynurenine treated: EKyn). Upon termination of the treatment, all rats received normal rodent chow until the animals were evaluated in adulthood (postnatal days 56-85). EKyn treatment resulted in increased extracellular KYNA and reduced extracellular glutamate in the hippocampus, measured by in vivo microdialysis, and caused impairments in hippocampus-dependent learning in adult rats. Acute administration of BFF816, a systemically active inhibitor of kynurenine aminotransferase II (KAT II), the major KYNA-synthesizing enzyme in the brain, normalized neurochemistry and prevented contextual memory deficits in adult EKyn animals. Collectively, these results demonstrate that acute inhibition of KYNA neosynthesis can overcome cognitive impairments that arise as a consequence of elevated brain KYNA in early brain development.
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