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.
Highlights
Depression is a devastating psychiatric disease characterized by anhedonia, low motivation, pessimism, and self-accusation[1]
Fluoxetine attenuated the decrease in number of astrocytes in chronic mild stress (CMS) model mice As shown in Fig. 1a, mice were subjected to CMS for about 5 weeks to establish depression model and followed by treatment with fluoxetine (10 mg/kg/day, i.p) for 4 weeks in the present study
It was found that the number of GFAP+ astrocytes decreased in hippocampus and cortex of CMS mice, while fluoxetine treatment attenuated the loss of astrocytes in CMS model (Fig. 1e)
Summary
Depression is a devastating psychiatric disease characterized by anhedonia, low motivation, pessimism, and self-accusation[1]. Recent report holds the perspective that neuronal autophagy plays a potential role in the pathophysiology and treatment of depression[7] and Official journal of the Cell Death Differentiation Association. The cell type with the largest number in central nervous system, whose pathological damage is involved in many neurological diseases[11]. It has been known that decrease in cellular number and volume of astrocytes in cortex and hippocampus plays an important role in the pathogenesis of major depression[12]. Mitophagy as a selective autophagy may play a crucial role in determining the fate of astrocytes in depression. It remains unclear the significance of astrocytic autophagy in the pathogenesis and treatment of depression
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