Sleep deprivation selectively down-regulates astrocytic 5-HT_2B receptors and triggers depressive-like behaviors via stimulating P2X₇ receptors

Abstract

Chronic loss of sleep damages health and disturbs quality of life. The long-lasting sleep deprivation (SD) as well as sleep abnormalities is a substantial risk factor for major depressive disorder (MDD), although the underlying mechanisms are not clear. In our previous studies, we report the activation of nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome induced by long-term SD is P2X₇ receptors (P2X₇R) dependent, and antidepressant fluoxetine could alleviate this neuroinflammasome via 5-HT_2B receptors (5-HT_2BR) in astrocytes. Here, we discovered that the chronic SD activates astroglial P2X₇ receptors, which in turn selectively down-regulated expression of 5-HT_2BR in astrocytes. Stimulation of P2X₇R induced by SD suppressed the phosphorylation of AKT and FoxO3a selectively in astrocytes, but not in neurones. The over-expression of FoxO3a in astrocytes inhibited expression of 5-HT_2BR. Down-regulation of 5-HT_2BR instigated by SD suppressed activation of STAT3 and relieved the inhibition of Ca²⁺-dependent phospholipase A2 (cPLA2). This latter cascade promoted the release of arachidonic acid (AA) and prostaglandin E2 (PGE2). The depressive-like behaviours induced by SD were alleviated in P2X₇R-KO mice. Our study reveals the mechanism underlying chronic SD-induced depressive-like behaviors and highlights that blocking P2X₇ receptors or activating 5-HT_2BR in astrocytes could play a key role for exploring the therapeutic strategies aimed at the depression evoked by sleep disorders.