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

Xiaowei Li,Maosheng Xia,Baoman Li,Alexei Verkhratsky,Shuai Li,Zexiong Li,Shanshan Liang

doi:10.3389/fpsyt.2018.00734

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.

Highlights

Sleep occupies almost one third of our life and it is necessary for human survival
We discovered that activation of nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasomes contributes to the development of the depressive-like behaviors induced by sleep deprivation (SD); the NLRP3 inflammasome was associated to the decreased level of brain-derived neurotrophic factor (BDNF)
Leptin increases the expression of 5-hydroxytryptamine receptor 2B (5-HT2B) receptors via leptin receptor (LepR)/JAK2/STAT3 pathway in astrocytes, and fluoxetine could be more effective to elevate the level of BDNF and improve the depressive-like behaviors via the increased 5-HT2B receptors induced by leptin (Figure 7)

Summary

Introduction

Sleep occupies almost one third of our life and it is necessary for human survival. Sleep loss results in various pathological manifestations, such as cognitive impairments [1], mood disorders [2], the increased circulating levels of inflammatory cytokines [3] and the dysfunction of the metabolite clearance from brain [4]. SD increases serum levels of brain-derived neurotrophic factor (BDNF) [8], which is related to sleep, cognition and learning [9,10,11], The BDNF released from astrocytes is known to be associated with mood disorders [10]. Both neuroinflamamtory [12] and the neurotrophin [10] hypothesis of MDD have been considered recently, albeit the links between inflammasome activation or BDNF secretion to the depressive symptoms induced by SD are unknown

Methods

Results

Conclusion