Astrocytes-induced neuronal inhibition contributes to depressive-like behaviors during chronic stress

Hao, Tianpao; Du, Xiaohong; Shen, Yang; Zhang, Yang; Liang, Feiyu

doi:10.1016/j.lfs.2020.118099

Cited by 18 publications

(10 citation statements)

References 53 publications

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“…Patients with MDD exhibit many features of inflammatory responses, including the increased levels of pro-inflammatory cytokines in peripheral blood, cerebrospinal fluid and brain structures as well as reactive microglia visualized by neuroimaging techniques [ 18 , 19 ]. Acute stress, such as lipopolysaccharide (LPS) and chronic social defeat stress (CSDS) stress, could induce the generation of A1 astrocytes in mice [ 20 , 21 ]. Nevertheless, it remains unclear the significance of A1 astrocyte in the pathogenesis and treatment of MDD.…”

Section: Introductionmentioning

confidence: 99%

Fluoxetine inhibited the activation of A1 reactive astrocyte in a mouse model of major depressive disorder through astrocytic 5-HT2BR/β-arrestin2 pathway

Fang

Ding

Zhang

et al. 2022

J Neuroinflammation

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Background Fluoxetine, a selective serotonin reuptake inhibitor, has been reported to directly bind with 5-HT2B receptor (5-HT2BR), but the precise mechanisms, whereby fluoxetine confers the anti-depressive actions via 5-HT2BR is not fully understood. Although neuroinflammation-induced A1 astrocytes are involved in neurodegenerative diseases, the role of A1 astrocyte in the pathogenesis and treatment of major depressive disorder (MDD) remains unclear. Methods Mice were subjected to chronic mild stress (CMS) for 6 weeks and subsequently treated with fluoxetine for 4 weeks. The depressive-like and anxiety-like behaviors and the activation of A1 reactive astrocyte in hippocampus and cortex of mice were measured. Primary astrocytes were stimulated with A1 cocktail (tumor necrosis factor (TNF)-α, interleukin (IL)-1α and C1q), activated (LPS) microglia-conditioned medium (MCM) or IL-6 for 24 h and the expression of A1-special and A2-special markers were determined using RT-qPCR and western blot. The role of 5-HT2BR in the effects of fluoxetine on A1 reactive astrocyte was measured using 5-HT2BR inhibitor and siRNA in vitro and AAVs in vivo. The functions of downstream signaling Gq protein and β-arrestins in the effects of fluoxetine on the activation of A1 astrocyte were determined using pharmacological inhibitor and genetic knockout, respectively. Results In this study, we found that fluoxetine inhibited the activation of A1 reactive astrocyte and reduced the abnormal behaviors in CMS mice, as well as ameliorated A1 astrocyte reactivity under three different stimulators in primary astrocytes. We also showed that astrocytic 5-HT2BR was required in the inhibitory effects of fluoxetine on A1 reactive astrocyte in MDD in vivo and in vitro. We further found that the functions of fluoxetine in the activation of A1 astrocyte were independent of either Gq protein or β-arrestin1 in vitro. β-arrestin2 pathway was the downstream signaling of astrocytic 5-HT2BR mediated the inhibitory effects of fluoxetine on A1 astrocyte reactivity in primary astrocytes and CMS mice, as well as the improved roles of fluoxetine in behavioral impairments of CMS mice. Conclusions These data demonstrate that fluoxetine restricts reactive A1 astrocyte via astrocytic 5-HT2BR/β-arrestin2 pathway in a mouse model of MDD and provide a novel therapeutic avenue for MDD.

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Section: Introductionmentioning

confidence: 99%

Fluoxetine inhibited the activation of A1 reactive astrocyte in a mouse model of major depressive disorder through astrocytic 5-HT2BR/β-arrestin2 pathway

Fang

Ding

Zhang

et al. 2022

J Neuroinflammation

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“…[ 45 ] Microglial changes were mainly observed in the Isocortex and HIP regions, while astrocyte changes were mainly observed in the AMY and OLF regions. Chronic stress induces hyperactivation and structural alterations of microglia, [ 46 ] astrocyte branch morphology changes, [ 47 , 48 ] astrocytes, and microglia are important players in mediating neuroinflammatory like responses, synaptic dysfunction, and BBB impairment. [ 43 ] Increased microglia‐neuron interactions have been reported in the motor cortex of susceptible mice.…”

Section: Resultsmentioning

confidence: 99%

Spatial transcriptomic analysis of the mouse brain following chronic social defeat stress

Wang,

Song,

Zhao

et al. 2023

Exploration

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Depression is a highly prevalent and disabling mental disorder, involving numerous genetic changes that are associated with abnormal functions in multiple regions of the brain. However, there is little transcriptomic‐wide characterization of chronic social defeat stress (CSDS) to comprehensively compare the transcriptional changes in multiple brain regions. Spatial transcriptomics (ST) was used to reveal the spatial difference of gene expression in the control, resilient (RES) and susceptible (SUS) mouse brains, and annotated eight anatomical brain regions and six cell types. The gene expression profiles uncovered that CSDS leads to gene synchrony changes in different brain regions. Then it was identified that inhibitory neurons and synaptic functions in multiple regions were primarily affected by CSDS. The brain regions Hippocampus (HIP), Isocortex, and Amygdala (AMY) present more pronounced transcriptional changes in genes associated with depressive psychiatric disorders than other regions. Signalling communication between these three brain regions may play a critical role in susceptibility to CSDS. Taken together, this study provides important new insights into CSDS susceptibility at the ST level, which offers a new approach for understanding and treating depression.

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“…Moreover, A1-like astrocytes are less capable of promoting the formation of new synapses, causing a reduction in the excitatory function of CNS neurons [40]. In recent studies, A1-like astrocytes are associated with depressive behaviors triggered via multiple animal models of depression [14,15,41]. However, the exact mechanism and intervention of A1-like astrocyte in MDD are still lacking.…”

Section: Discussionmentioning

confidence: 99%

“…Coincidentally, MDD patients have plentiful inflammatory traits, including elevated proinflammatory cytokines in the brain, cerebrospinal fluid, and peripheral blood, together with the neuroimaging visualization of reactive microglia [13]. Moreover, recent reports have demonstrated that the A1-like astrocytes are induced by lipopolysaccharide (LPS)-induced acute stress and chronic social defeat stress (CSDS) [14,15]. Despite these findings, the significance of A1-like astrocytes in the pathogenesis and management of MDD still becomes uncertain.…”

Section: Introductionmentioning

confidence: 99%

Blocking Two-Pore Domain Potassium Channel TREK-1 Inhibits the Activation of A1-Like Reactive Astrocyte Through the NF-κB Signaling Pathway in a Rat Model of Major Depressive Disorder

et al. 2023

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Major depressive disorder (MDD) refers to a widespread psychiatric disorder. Astrocytes play a pivotal role in regulating inflammation which is a well-acknowledged key component in depression pathogenesis. However, the effects of the neuroinflammation-inducing A1-like astrocytes on MDD are still unknown. TWIK-related K+ channel 1 (TREK-1) has been demonstrated to regulate the action of antidepressants. Nevertheless, its mechanisms and effects on A1-like astrocyte stimulation in MDD are not clear. Therefore, we conducted in vivo and in vitro experiments using TREK-1 specific inhibitor spadin. In vivo, rats were subjected to a 6-week chronic unpredictable mild stress (CUMS) followed by spadin treatment. Behavioral tests were employed to surveil depressive-like behaviors. Hippocampal proteomic analysis was carried out with the purpose of identifying differentially expressed proteins after CUMS and spadin treatments. In vitro, astrocyte-conditioned medium and spadin were used to treat rat astrocyte cell line. The activated microglia, inflammatory factors, A1 astrocyte markers, and activated nuclear factor kappa B (NF-κB) pathway were later analyzed using immunofluorescence, western blot, and RT-qPCR. Our findings indicated that blockage of TREK-1 reduced CUMS-induced depressive-like behavior in rats, inhibited the microglial stimulation, reduced inflammatory factor levels, and suppressed the activation of A1-like reactive astrocytes in the hippocampus. We also verified that the suppression of A1-like astrocytes by spadin necessitated the NF-κB pathway. According to the findings, blocking TREK-1 inhibited the activation of A1-like reactive astrocytes via the NF-κB signaling pathway in MDD. Our study preliminarily identifies a novel antidepressant mechanism of TREK-1 action and provides a therapeutic path for MDD.

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Astrocytes-induced neuronal inhibition contributes to depressive-like behaviors during chronic stress

Cited by 18 publications

References 53 publications

Fluoxetine inhibited the activation of A1 reactive astrocyte in a mouse model of major depressive disorder through astrocytic 5-HT2BR/β-arrestin2 pathway

Fluoxetine inhibited the activation of A1 reactive astrocyte in a mouse model of major depressive disorder through astrocytic 5-HT2BR/β-arrestin2 pathway

Spatial transcriptomic analysis of the mouse brain following chronic social defeat stress

Blocking Two-Pore Domain Potassium Channel TREK-1 Inhibits the Activation of A1-Like Reactive Astrocyte Through the NF-κB Signaling Pathway in a Rat Model of Major Depressive Disorder

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