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

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-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.

The neuroprotective mechanism of lithium after ischaemic stroke

“…Staining was visualised by electrochemiluminescence (ECL) detection reagents and were 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 65 .…”

Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor

“…All of these indicate that the downregulation of the astroglial 5-HT 2B R may promote the development of depressive behavior in Parkinson's disease. In addition, astroglial 5-HT 2B R was also found to play a role in depressive behavior associated with sleep deprivation [99,100]. Specifically, the expression of the 5-HT 2B R in a sleep deprivation mouse model was downregulated selectively in astrocytes, which was controlled by the activation of the P2X7 receptor [99].…”

“…In addition, astroglial 5-HT 2B R was also found to play a role in depressive behavior associated with sleep deprivation [99,100]. Specifically, the expression of the 5-HT 2B R in a sleep deprivation mouse model was downregulated selectively in astrocytes, which was controlled by the activation of the P2X7 receptor [99]. Interestingly, leptin was found to increase the expression of astrocytic 5-HT 2B Rs and thus enhance the action of fluoxetine on depressive-like behaviors induced by sleep deprivation [100].…”

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“…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 .…”