beta-arrestin 2 is essential for fluoxetine-mediated promotion of hippocampal neurogenesis in a mouse model of depression
- 30 April 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Acta Pharmacologica Sinica
- Vol. 42 (5), 679-690
- https://doi.org/10.1038/s41401-020-00576-2
Abstract
Over the last decade, the roles of beta-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 beta-arrestin2(-/-) mice and cultured adult neural stem cells (ANSCs) to investigate the involvement of the 5-HT receptor-beta-arrestin axis in the pathogenesis of depression and in the therapeutic effect of fluoxetine. We found that beta-arrestin2 deletion abolished the fluoxetine-mediated improvement in depression-like behaviors and monoamine neurotransmitter levels, although beta-arrestin2 knockout did not aggravate CMS-induced changes in mouse behaviors and neurotransmitters. Notably, the beta-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 beta-arrestin2 knockout decreased the number of proliferating cells in the hippocampal dentate gyrus and suppressed the proliferative capability of ANSCs in vitro. Moreover, beta-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-beta-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.This publication has 45 references indexed in Scilit:
- Stress and glucocorticoids promote oligodendrogenesis in the adult hippocampusMolecular Psychiatry, 2014
- Aquaporin‐4 Knockout Exacerbates Corticosterone‐Induced Depression by Inhibiting Astrocyte Function and Hippocampal NeurogenesisCNS Neuroscience & Therapeutics, 2014
- β-Arrestin2 plays a key role in the modulation of the pancreatic beta cell mass in miceDiabetologia, 2013
- From Pathophysiology to Novel Antidepressant Drugs: Glial Contributions to the Pathology and Treatment of Mood DisordersBiological Psychiatry, 2013
- The role of GRK6 in animal models of Parkinson's Disease and L-DOPA treatmentScientific Reports, 2012
- Essential requirement for β-arrestin2 in mouse intestinal tumors with elevated Wnt signalingProceedings of the National Academy of Sciences of the United States of America, 2012
- The Neuropeptide Oxytocin Facilitates Pro-Social Behavior and Prevents Social Avoidance in Rats and MiceNeuropsychopharmacology, 2011
- Rates of Major Depressive Disorder and Clinical Outcomes Following Traumatic Brain InjuryJAMA, 2010
- Neurogenesis-Dependent and -Independent Effects of Fluoxetine in an Animal Model of Anxiety/DepressionNeuron, 2009
- Purification and properties of glutathione reductase of human erythrocytesBiochimica et Biophysica Acta (BBA) - Enzymology, 1969