Abstract
Abstract Introduction Sleep disorders and cognitive dysfunction often afflict the general population and are common amongst patients with neuropsychiatric disorders like schizophrenia. Sleep deprivation (SD) disrupts cognitive function, yet little is known about underlying mechanisms. The tryptophan metabolite kynurenic acid (KYNA), an endogenous a7nACh and NMDA receptor antagonist, is synthesized by kynurenine aminotransferase II (KAT II). KYNA is increased in the brain of patients with schizophrenia and our translational studies demonstrate that elevated KYNA disrupts hippocampal learning and sleep architecture in rodents (Pocivavsek et al. 2017 Sleep). We hypothesize a mechanistic link between KYNA, sleep, and cognitive dysfunction. Methods In vivo microdialysis in the dorsal hippocampus and simultaneous EEG/EMG telemetry was conducted in adult male Wistar rats (N=3-5 per group). Using a within-subjects experimental design, rats underwent a control and SD day. Animals received either vehicle or KAT II inhibitor PF-04859989 (PF), 30mg/kg s.c., on both days at zeitgeber time (ZT) 0 or ZT6. SD occurred from ZT0-6 by gentle handling. KYNA levels were evaluated in the microdialysate. Results SD effectively eliminated REM sleep (100%) and significantly reduced NREM (94%) during ZT0-6. Extracellular KYNA levels in the hippocampus significantly increased with SD (2-way ANOVA, time x SD: **P<0.0001) and PF readily prevented this accumulation. Initial sleep recovery (ZT6-12) did not significantly differ between treatment groups. During the dark phase (ZT12-24), PF treatment of SD animals promoted REM sleep parameters, including total REM duration (2-way ANOVA, SD x treatment ZT: P<0.05). PF treatment enhanced theta spectral power determined by Discrete Fourier transform during REM sleep recovery (ZT12-24). PF alone during the control day enhanced NREM delta power (P<0.05) during the late light phase (ZT6-12). Conclusion Importantly, the KAT II inhibitor PF promoted sleep recovery following acute SD, supporting our hypothesis that the accumulation of KYNA may exacerbate sleep disruptions. Changes in sleep parameters elicited by PF, a potential therapeutic avenue, may be indicative of mild somnolence. The present and future complementary experiments with cognitive behavioral tasks in rodents support our understanding of the role of KYNA in modulating sleep and cognition. Support (If Any) National Institutes of Health Grant No. NIH R01 NS102209
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
