Sleep Deprivation Selectively Down-Regulates Astrocytic 5-HT2BReceptors and Triggers Depressive-Like Behaviors via Stimulating P2X7 Receptors in Mice
Maosheng Xia 1,2 • Zexiong Li1 • Shuai Li1 • Shanshan Liang1 • Xiaowei Li1 • Beina Chen 1 • Manman Zhang1 • Chengyi Dong2 • Alexei Verkhratsky 1,3 • Dawei Guan4 • Baoman Li 1,5
1 Practical Teaching Centre, School of Forensic Medicine, China Medical University, Shenyang 110122, China
2 Department of Orthopaedics, The First Hospital, China Medical University, Shenyang 110001, China
3 Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M139PL, UK
4 Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang 110122, China
5 Department of Poison Analysis, School of Forensic Medicine, China Medical University, Shenyang 110122, China
Abstract
Chronic loss of sleep damages health and disturbs the quality of life. Long-lasting sleep deprivation (SD) as well as sleep abnormalities are substantial risk factors for major depressive disorder, although the underlying mechanisms are not clear. Here, we showed that chronic SD in mice promotes a gradual elevation of extracellular ATP, which activates astroglial P2X7 receptors (P2X7Rs). Activated P2X7Rs, in turn, selectively down-regulated the expression of 5-HT2B receptors (5-HT2BRs) in astrocytes. Stimulation of P2X7Rs induced by SD selectively suppressed the phosphorylation of AKT and FoxO3a in astrocytes, but not in neurons. The over-expression of FoxO3a in astrocytes inhibited the expression of 5-HT2BRs. Down-regulation of 5-HT2BsRs instigated by SD suppressed the activation of STAT3 and relieved the inhibition of Ca2+-dependent phospholipase A2. This latter cascade promoted the release of arachidonic acid and prostaglandin E2. The depression-like behaviors induced by SD were alleviated in P2X7R-KO mice. Our study reveals the mechanism underlying chronic SD-induced depression-like behaviors and suggests 5-HT2BRs as a key target for exploring therapeutic strategies aimed at the depression evoked by sleep disorders.
Keywords
Astrocyte; Sleep deprivation; P2X7 receptor; 5-HT2B receptor; FoxO3a
