MeCP2 controls hippocampal brain-derived neurotrophic factor expression via homeostatic interactions with...

Major depressive disorder (MDD) is a considerable public health concern, which affects patients worldwide. MDD is associated with psychosocial impairment, poor quality of life, and significant disability, morbidity and mortality. Stress is a major factor in depression, which impairs the structural and functional plasticity of the hippocampus. Previous studies have demonstrated that chronic unpredictable mild stress is able to downregulate the expression of brain‑derived neurotrophic factor (BDNF) and methyl‑CpG‑binding protein 2 (MeCP2), and alter the expression levels of certain microRNAs (miR). The aim of the present study was to investigate the regulatory association between BDNF, MeCP2 and miR-132 in an animal model of chronic stress‑induced depression. ELISA, western blot and qPCR were used to detect the expression levels of BDNF, MeCP2 and miR-132 in the peripheral blood samples of patients with MDD and in the hippocampi of depressed animals. In addition, a dual luciferase reporter gene system was used to determine whether miR-132 directly targets BDNF or MeCP2. The present study demonstrated that, as compared with normal subjects, miR‑132 expression was increased in the peripheral blood samples of patients with MDD, whereas the expression of MeCP2 and BDNF was decreased; thus, the expression levels of MeCP2 and BDNF were negatively correlated with those of miR‑132. In addition, in an animal model of chronic stress‑induced depression, increased expression levels of miR‑132, and decreased levels of MeCP2 and BDNF were detected in the hippocampi. Furthermore, knockdown of MeCP2 expression in primary hippocampal neurons increased the expression of miR‑132 and decreased the expression levels of BDNF. The results of the present study demonstrated that miR‑132 may directly target MeCP2, but not BDNF, and control its expression at the transcriptional and translational level. miR‑132 was also shown to negatively regulate BDNF expression. The reduced expression levels of BDNF, as induced by MeCP2 knockdown, were enhanced by miR‑132 mimics, and were rescued by miR‑132 inhibitors. These results suggested that homeostatic interactions between MeCP2 and miR‑132 may regulate hippocampal BDNF levels, which may have a role in the pathogenesis of MDD.