Over the last decade, the roles of β-arrestins in the treatment of neuropsychological diseases have become increasingly appreciated. Fluoxetine is the first selective serotonin reuptake inhibitor developed and is approved for the clinical treatment of depression. Emerging evidence suggests that fluoxetine can directly combine with the 5-HT receptor, which is a member of the G protein-coupled receptor (GPCR) family, in addition to suppressing the serotonin transporter. In this study, we prepared a chronic mild stress (CMS)-induced depression model with β-arrestin2−/− mice and cultured adult neural stem cells (ANSCs) to investigate the involvement of the 5-HT receptor-β-arrestin axis in the pathogenesis of depression and in the therapeutic effect of fluoxetine. We found that β-arrestin2 deletion abolished the fluoxetine-mediated improvement in depression-like behaviors and monoamine neurotransmitter levels, although β-arrestin2 knockout did not aggravate CMS-induced changes in mouse behaviors and neurotransmitters. Notably, the β-arrestin2−/− mice had a shortened dendritic length and reduced dendritic spine density, as well as decreased neural precursor cells, compared to the WT mice under both basal and CMS conditions. We further found that β-arrestin2 knockout decreased the number of proliferating cells in the hippocampal dentate gyrus and suppressed the proliferative capability of ANSCs in vitro. Moreover, β-arrestin2 knockout aggravated the impairment of cell proliferation induced by corticosterone and further blocked the fluoxetine-mediated promotion of mouse hippocampal neurogenesis. Mechanistically, we found that the 5-HT2BR-β-arrestin2-PI3K/Akt axis is essential to maintain the modulation of hippocampal neurogenesis in depressed mice. Our study may provide a promising target for the development of new antidepressant drugs.
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We would like to thank Prof. Gang Pei in Tongji University for providing β-arrestin2 knockout mice. The work reported herein was supported by the grants from the National Natural Science Foundation of China (No. 81922066, No. 81773706, No. 81991523, and No. 81630099) and the Drug Innovation Major Project (No. 2018ZX09711001-003-007).
The authors declare no competing interests.
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Li, Cx., Zheng, Y., Zhu, H. et al. β-arrestin 2 is essential for fluoxetine-mediated promotion of hippocampal neurogenesis in a mouse model of depression. Acta Pharmacol Sin 42, 679–690 (2021). https://doi.org/10.1038/s41401-020-00576-2
- neural stem cell