Leptin Increases Expression of 5-HT2B Receptors in Astrocytes Thus Enhancing Action of Fluoxetine on the Depressive Behavior Induced by Sleep Deprivation

Abstract

The long-lasting loss of sleep is a generally acknowledged risk factor for the occurrence of major depressive disorder (MDD), whereas sleep abnormalities being a key clinic symptom of the MDD. In our previous work, we demonstrated that the sleep deprivation (SD) stimulates activation of nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasomes as well as the release of IL-1β and IL-18 from astrocytes. However, the underlying mechanism connecting SD and MDD still requires further study. Apart of the secretion of the pro-inflammatory cytokines, SD affects production of brain-derived neurotrophic factor (BDNF) while release of BDNF from astrocytes appears a key contributor to mood disorders. If and how the activation of NLRP3 inflammasome following SD affects the level of BDNF remains unknown. Antidepressant fluoxetine acts through astroglial 5-hydroxytryptamine receptor 2B (5-HT2B); these receptors are also related to the sleep-wake cycle. Contribution of leptin to MDD has been discovered recently, although the mechanistic links between leptin and the depressive-like behaviors has not been revealed. In this study, we discovered: (i) that activation of NLRP3 inflammasome was involved in the depressive-like behaviors induced by SD; (ii) decrease in BDNF following SD required the activation of NLRP3 inflammasomes; (iii) leptin augmented the anti-depressive action of fluoxetine through an increase in expression of astrocytic 5-HT2B receptors. We suggest that decrease in BDNF by the activated NLRP3 inflammasomes in astrocytes is the key pathological event of the depressive-like behaviors induced by SD, while the combined treatment with fluoxetine and leptin improves therapeutic outcome for the depression induced by SD.

Fluoxetine improves behavioural deficits induced by chronic alcohol addiction by alleviating RNA editing of 5-HT2C receptors in astrocytes

“…Treatment with various concentration of fluoxetine regulates the expression of cFos through the opposite effects of PI3K/AKT and MAPK/ERK signalling pathways in astrocytes. The cFos is a transcription factor which regulates expression of several genes, such as caveolin-1 and BDNF 15,16,37 . Here we found that fluoxetine at 1 M suppressed the expression of ADAR2 increased by alcohol by regulating cFos through Src-mediated transactivation of EGFR and the downstream PI3K/AKT signalling pathway in astrocytes.…”

“…Alcohol abuse, however, can affect not only neuronal networks but also act on astrocytes, which are primarily responsible for homeostasis and catabolism of central neurotransmitters [9][10][11] . According to our previous studies, dysfunction of astrocytes contributes to pathophysiology of MDD, while SSRI antidepressant fluoxetine acts as an agonist of 5-HT2BR in astrocytes; this action being linked to fluoxetine anti-depressive activity [12][13][14][15][16] . Fluoxetine selectively increases the expression of 5-HT2BR in astrocytes, and up-regulates 5-HT2CR expression in neurones in conditions of chronic unpredictable mild stress (CUMS) 17 .…”

Update of inflammasome activation in microglia/macrophage in aging and aging‐related disease

“…Proper physical exercise would prevent the induction of inflammasome . Sound sleep also helps to keep inflammasome quiescent . Confronting the aging‐related CNS diseases, targeting inflammasome is a promising therapeutic strategy.…”

“…88 Sound sleep also helps to keep inflammasome quiescent. 89 Confronting the aging-related CNS diseases, targeting inflammasome is a promising therapeutic strategy. A broad body of F I G U R E 4 Interactions of inflammasome in microphage with neural inflammation and aging-related diseases.…”

Sleep deprivation selectively down-regulates astrocytic 5-HT2B receptors and triggers depressive-like behaviors via stimulating P2X7 receptors

“…The 5-HT2BRs are related to the major depressive disorder (MDD); these receptors expressed in astrocytes are targets for serotonin-specific re-uptake inhibitors (SSRIs) (Li,5 Zhang, Li, Hertz, & Peng, 2009;Li, Zhang, Zhang, Hertz, & Peng, 2011;Li et al, 2008;Li et al, 2018;Peng, Gu, Li, & Hertz, 2014;Peng, Song, Li, & Verkhratsky, 2018).…”