Abstract
MicroRNAs (miRNAs) are noncoding RNAs that participate in the pathophysiology of depression by targeting many functional genes. As shown in our previous study, chronic stress up-regulates miR-34a in the hippocampus. However, little is known about the mechanism by which miR-34a regulates the process of depression or its functions as an antidepressant by regulating its targets. In the present study, the dynamic alterations in miR-34a expression and the mechanism underlying miR-34a regulation were assessed after the administration of the antidepressant fluoxetine to mice exposed to chronic stress. In addition, the effects of miR-34a inhibition on mice were directly evaluated. Both lipopolysaccharide (LPS) and corticosterone treatment caused depression-like symptoms and increased miR-34a expression. Additionally, the expression of miR-34a, which was regulated by tropomyosin receptor kinase B (TrkB)/MEK1/ERK signaling, was consistent with the onset of action of fluoxetine. A luciferase reporter assay identified synaptotagmin-1 and Bcl-2 as the targets of miR-34a. Moreover, a miR-34a antagomir exerted antidepressant-like effects, activated TrkB/MEK1/ERK signaling and improved spine morphology in the hippocampus. In conclusion, hippocampal miR-34a overexpression was a typical feature in depression-like animals, and miR-34a downregulation exerts antidepressant-like effects by restoring the spine morphology through its target synaptotagmin-1.