PT - JOURNAL ARTICLE AU - Xia, Maosheng AU - Li, Shuai AU - Liang, Shanshan AU - Li, Xiaowei AU - Li, Zexiong AU - Verkhratsky, Alexei AU - Guan, Dawei AU - Li, Baoman TI - Sleep deprivation selectively down-regulates astrocytic 5-HT<sub>2B</sub> receptors and triggers depressive-like behaviors via stimulating P2X<sub>7</sub> receptors AID - 10.1101/745505 DP - 2019 Jan 01 TA - bioRxiv PG - 745505 4099 - http://biorxiv.org/content/early/2019/08/23/745505.short 4100 - http://biorxiv.org/content/early/2019/08/23/745505.full AB - 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-HT2B receptors (5-HT2BR) in astrocytes. Here, we discovered that the chronic SD activates astroglial P2X7 receptors, which in turn selectively down-regulated expression of 5-HT2BR 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-HT2BR. Down-regulation of 5-HT2BR 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-HT2BR in astrocytes could play a key role for exploring the therapeutic strategies aimed at the depression evoked by sleep disorders.Main Points Chronic SD selectively down-regulates expression of 5-HT2BR through activation of P2X7R in astrocytes. SD promotes the release of AA and PGE2 via the decreased 5-HT2BR, these factors induce depressive-like behaviors.SDsleep deprivation;MDDmajor depressive disorder;NLRP3nucleotide-binding domain and leucine-rich repeat protein-3;P2X7RP2X7 receptors;5-HT2BR5-HT2B receptors;FoxO3aForkhead box O3a;cPLA2Ca2+-dependent phospholipase A2;AAarachidonic acid;PGE2prostaglandin E2;ATPadenosine-tri-phosphate;SSRIsserotonin-specific re-uptake inhibitors;5-HT5-hydroxytryptamine;EGFRepidermal growth factor receptor;TCAtrichloroacetic acid;DMEMDulbecco’s modified Eagle’s medium;dBcAMPdibutyryl cyclic AMP;PFAparaformaldehyde;GAPDHglyceraldehyde 3-phosphate dehydrogenase;GFPgreen fluorescent protein;TSTTail suspension test;FSTForced swimming test;COXcyclooxygenase;WTwild type