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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 P2X 7 receptors (P2X 7 Rs). Activated P2X 7 Rs, in turn, selectively down-regulated the expression of 5-HT 2B receptors (5-HT 2B Rs) in astrocytes. Stimulation of P2X 7 Rs 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-HT 2B Rs. Down-regulation of 5-HT 2Bs Rs instigated by SD suppressed the activation of STAT3 and relieved the inhibition of Ca 2+ -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 P2X 7 R-KO mice. Our study reveals the mechanism underlying chronic SD-induced depression-like behaviors and suggests 5-HT 2B Rs as a key target for exploring therapeutic strategies aimed at the depression evoked by sleep disorders.

Sleep Deprivation Selectively Down-Regulates Astrocytic 5-HT2B Receptors and Triggers Depressive-Like Behaviors via Stimulating P2X7 Receptors in Mice