Calcineurin governs baseline and homeostatic regulations of non-rapid eye movement sleep in mice

• 成果类型: Article
• 署名作者: Yin, Xin; Zhang, Zihan; Zhou, Rui; Zuo, Peng; Sang, Di; Zhou, Shuang; Shi, Bihan; Chen, Lin; Wu, Chongyang; Guo, Ying; Wang, Fengchao; Zhang, Eric Erquan; Li, Qi; Yanagisawa, Masashi; Liu, Qinghua
• 署名单位: Peking University; National Institute of Biological Sciences, Beijing; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; Tsinghua University; Beijing Normal University; Tsinghua University; University of Tsukuba; Tsinghua University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8780
• DOI: 10.1073/pnas.2418317122
• 发表日期: 2025-01-28
• 关键词: dependent protein-kinase; phosphatase; neurons; drosophila; potentiation; involvement; activation; cascade; drive; need

摘要

Sleep need accumulates during waking and dissipates during sleep to maintain sleep homeostasis (process S). Besides the regulation of daily (baseline) sleep amount, homeostatic sleep regulation commonly refers to the universal phenomenon that sleep deprivation (SD) causes an increase of sleep need, hence, the amount and intensity of subsequent recovery sleep. The central regulators and signaling pathways that govern the baseline and homeostatic sleep regulations in mammals remain unclear. Here, we report that enhanced activity of calcineurin A alpha (CNA alpha)-a catalytic subunit of calcineurin-in the mouse brain neurons sharply increases the amount (to similar to 17-h/d) and delta power-a measure of intensity-of non-rapid eye movement sleep (NREMS). Knockout of the regulatory (CnB1) or catalytic (CnA alpha and CnA beta) subunits of calcineurin diminishes the amount (to similar to 4-h/d) and delta power of baseline NREMS, but also nearly abrogates the homeostatic recovery NREMS following SD. Accordingly, mathematical modeling of process S reveals an inability to accumulate sleep need during spontaneous or forced wakefulness in calcineurin deficient mice. Moreover, calcineurin promotes baseline NREMS by antagonizing wake- promoting protein kinase A and, in part, by activating sleep- promoting kinase SIK3. Together, these results indicate that calcineurin is an important regulator of sleep need and governs both baseline and homeostatic regulations of NREMS in mice.