The effect of fluoxetine on astrocyte autophagy flux and injured mitochondria clearance in a mouse model of depression

Abstract

Although multiple hypotheses had been proposed to clarify the causes of depression, the accurate pathogenesis and effective treatment of depression still need to be solved. Pathological change of astrocytes has been recognized to play a pivotal role in depression. Fluoxetine is the first selective serotonin reuptake inhibitor, however, the underlying mechanisms of fluoxetine are incompletely excavated. Emerging evidence shows that fluoxetine promotes autophagic processes in tumor cells. However, whether astrocytic autophagy gets involved in the cytoprotection of fluoxetine on astrocytes in depression treatment remains unexplored. Here we prepared chronic mild stress (CMS)-induced mouse model and treated mice with fluoxetine (10 mg/kg) for 4 weeks to determine the correlation between proautophagic effect of fluoxetine and astrocyte protection in depression. Primary hippocampal astrocytes were cultured to investigate the potential mechanism of fluoxetine in regulating astrocyte autophagy. We found that fluoxetine (10 mg/kg) treatment promoted autophagosome formation and increased clearance of injured mitochondria, consequently protected astrocytes in CMS model mice. Fluoxetine (10 μM) could also promote the autophagic flux unblocked via enhancing fusion of autophagosomes with lysosomes in primary astrocytes. Moreover, fluoxetine promoted mitophagy by increased colocalization of autophagosomes and mitochondria, eliminating damaged mitochondria in corticosterone-treated astrocytes. Further in vitro study showed that p53 presence is required for fluoxetine activated autophagy flux and fluoxetine promotes astrocytic autophagy in a p53-dependent mechanism. Collectively, this work gives us insights into a novel approach to treat depression depending on astrocytes, and provides a promising molecular target for the development of antidepressant drugs besides regulating neurotransmitters.

Activation of astrocytic sigma‐1 receptor exerts antidepressant‐like effect via facilitating CD38‐driven mitochondria transfer

“…In the past few decades, most of the anti-MDD targets are considered to act on neurons such as monoaminergic, glutamatergic or GABAergic neurons, although recently growing bodies of studies reveal astrocytic responses to antidepressants (Cui et al, 2018;Shu et al, 2019). In the present study, we demonstrated Sig-1R can directly act on astrocyte to elicit antidepressant activity.…”

The Contribution of Astrocyte Autophagy to Systemic Metabolism

“…In addition, the antidepressant fluoxetine protects cultured astrocytes from the deleterious effect of corticosterone through the induction of autophagic flux. Fluoxetine concretely increases mitophagy, which allows the elimination of damaged mitochondria and alleviates ROS production induced by corticosterone in astrocytes [83].…”

<p>Weighted Gene Coexpression Network Analysis Identifies Specific Modules and Hub Genes Related to Major Depression</p>

“…43,44 One finding supporting the role of antidepressants in autophagy was that fluoxetine (10 μM), a selective serotonin reuptake inhibitor (SSRI), could promote unblocked autophagic flux by enhancing the fusion of autophagosomes with lysosomes in primary astrocytes. 45 The tricyclic antidepressant amitriptyline was found to increase autophagy in primary neurons and astrocytes, similar to the selective serotonin reuptake inhibitor fluoxetine. A further expanded study found that amitriptyline and fluoxetine lead to the gradual accumulation of sphingomyelin in lysosomes, which stimulates autophagy via protein phosphatase 2A, ULK, Beclin, and LC3B.…”