期刊
SCHIZOPHRENIA BULLETIN
卷 47, 期 5, 页码 1320-1330出版社
OXFORD UNIV PRESS
DOI: 10.1093/schbul/sbab029
关键词
kynurenic acid; sex differences; REM sleep; NREM sleep; tryptophan
类别
资金
- National Institutes of Health [NIH R01 NS102209, P50 MH103222]
- University of South Carolina (Magellan Scholar and Science Undergraduate Research Fellowships)
The study found that prenatal kynurenine exposure induces sex-specific changes in sleep-wake behavior, arousal, and KP metabolism in offspring.
Dysregulation of the kynurenine pathway (KP) of tryptophan catabolism has been implicated in psychotic disorders, including schizophrenia and bipolar disorder. Kynurenic acid (KYNA) is a KP metabolite synthesized by kynurenine aminotransferases (KATs) from its biological precursor kynurenine and acts as an endogenous antagonist of N-methyl-D-aspartate and alpha 7-nicotinic acetylcholine receptors. Elevated KYNA levels found in postmortem brain tissue and cerebrospinal fluid of patients are hypothesized to play a key role in the etiology of cognitive symptoms observed in psychotic disorders. Sleep plays an important role in memory consolidation, and sleep disturbances are common among patients. Yet, little is known about the effect of altered KP metabolism on sleep-wake behavior. We presently utilized a well-established experimental paradigm of embryonic kynurenine (EKyn) exposure wherein pregnant dams are fed a diet laced with kynurenine the last week of gestation and hypothesized disrupted sleep-wake behavior in adult offspring. We examined sleep behavior in adult male and female offspring using electroencephalogram and electromyogram telemetry and determined sex differences in sleep and arousal in EKyn offspring. EKyn males displayed reduced rapid eye movement sleep, while female EKyn offspring were hyperaroused compared to controls. We determined that EKyn males maintain elevated brain KYNA levels, while KYNA levels were unchanged in EKyn females, yet the activity levels of KAT I and KAT II were reduced. Our findings indicate that elevated prenatal kynurenine exposure elicits sex-specific changes in sleep-wake behavior, arousal, and KP metabolism.
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