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.

MicroRNA（miRNA）是非编码RNA，通过靶向许多功能基因参与抑郁症的病理生理。如我们先前的研究所示，慢性应激会上调海马中的miR-34a。但是，关于miR-34a通过调节其靶标调节抑郁过程或其作为抗抑郁药的功能的机制知之甚少。在本研究中，对暴露于慢性应激的小鼠服用抗抑郁药氟西汀后，评估了miR-34a表达的动态变化和miR-34a调控的基本机制。此外，直接评估了miR-34a抑制对小鼠的影响。脂多糖（LPS）和皮质酮治疗均引起抑郁样症状并增加miR-34a表达。此外，miR-34a的表达 它由原肌球蛋白受体激酶B（TrkB）/ MEK1 / ERK信号传导调节，与氟西汀起效相一致。萤光素酶报告基因分析鉴定突触突触素-1和Bcl-2为miR-34a的靶标。此外，miR-34a antagomir发挥抗抑郁样作用，激活TrkB / MEK1 / ERK信号传导并改善海马的脊柱形态。总之，海马miR-34a过表达是抑郁症样动物的典型特征，miR-34a下调通过其靶突触突触素1恢复脊柱形态而发挥抗抑郁样作用。miR-34a antagomir发挥抗抑郁样作用，激活TrkB / MEK1 / ERK信号传导并改善海马的脊柱形态。总之，海马miR-34a过表达是抑郁症样动物的典型特征，miR-34a下调通过其靶突触突触素1恢复脊柱形态而发挥抗抑郁样作用。miR-34a antagomir发挥抗抑郁样作用，激活TrkB / MEK1 / ERK信号传导并改善海马的脊柱形态。总之，海马miR-34a过表达是抑郁症样动物的典型特征，miR-34a下调通过其靶突触突触素1恢复脊柱形态而发挥抗抑郁样作用。