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

Abstract

Running title: Sleep deprivation reduces 5-HT2BR via P2X7R Total word count: 4,317; word count of Introduction: 447; word count of Material and Methods: 1,445; word count of Results: 1,355; word count of Discussion: 847. #Thees authors contributed equally to this work. AbstractChronic 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 downregulated 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 Ca 2+ -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 PointsChronic 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.Abbreviations SD, sleep deprivation; MDD, major depressive disorder; NLRP3, nucleotide-binding domain and leucine-rich repeat protein-3; P2X7R, P2X7 receptors; 5-HT2BR, 5-HT2B

Ageing related thyroid deficiency increases brain-targeted transport of liver-derived ApoE4-laden exosomes leading to cognitive impairments

“…Staining was visualised by ECL detection reagents and was analysed with an Electrophoresis Gel Imaging Analysis System (MF-ChemiBIS 3.2, DNR Bio-Imaging Systems, Israel). Band density was measured with Window AlphaEaseTM FC 32-bit software 42 .…”