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-HT_2B receptors (5-HT_2BRs) 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-HT_2BRs. Down-regulation of 5-HT_2BsRs 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-HT_2BRs as a key target for exploring therapeutic strategies aimed at the depression evoked by sleep disorders.

长期睡眠不足会损害健康并扰乱生活质量。长期睡眠剥夺 (SD) 以及睡眠异常是重度抑郁症的重要危险因素，尽管其潜在机制尚不清楚。在这里，我们发现小鼠的慢性 SD 会促进细胞外 ATP 的逐渐升高，从而激活星形胶质细胞 P2X ₇受体（P2X ₇ Rs）。反过来，活化的 P2X ₇ Rs 选择性地下调星形胶质细胞中 5-HT _2B受体 (5-HT _2B Rs) 的表达。P2X _{7 的}刺激SD 诱导的 Rs 选择性抑制星形胶质细胞中 AKT 和 FoxO3a 的磷酸化，但不抑制神经元中的磷酸化。FoxO3a 在星形胶质细胞中的过度表达抑制了 5-HT _2B Rs的表达。SD引起的 5-HT _2Bs Rs 的_下调抑制了 STAT3 的激活并解除了对 Ca ²⁺依赖性磷脂酶 A2的抑制。后一种级联促进了花生四烯酸和前列腺素 E2 的释放。在 P2X ₇ R-KO 小鼠中，SD 诱导的抑郁样行为得到缓解。我们的研究揭示了慢性 SD 诱导的抑郁样行为的潜在机制，并建议 5-HT _2B Rs 作为探索针对睡眠障碍引起的抑郁症的治疗策略的关键目标。