Tong Lei, Li Ming-Da, Nie Peng-Yin, Chen Yao, Chen Yu-Lu, Ji Li-Li
Department of Anatomy, College of Basic Medical Sciences, China Medical University, Shenyang, China.
Department of 1st Clinical Medicine, China Medical University, Shenyang, China.
Neurobiol Stress. 2021 Feb 25;14:100311. doi: 10.1016/j.ynstr.2021.100311. eCollection 2021 May.
Post-traumatic stress disorder (PTSD) is usually accompanied by anxiety symptoms and decreased expression of brain-derived neurotrophic factor (BDNF), which played an important role in promoting neuronal proliferation and survival. Methyl CpG-binding protein 2 (MeCP2) is a positive mediator of BDNF and is regulated by miR-132-3p. In the present study, we explored the possible molecular mechanism of miR-132, focusing on the involvement of MeCP2 and BDNF in the formation of anxiety-like symptoms of PTSD. Single prolonged stress (SPS) was used to establish a model of PTSD in adult rats and the anxiety-like behavior was tested by the elevated plus-maze (EPM). The level of miR-132 in the prefrontal cortex (PFC) was increased and intraventricular injection of anti-miR-132 could significantly improve the anxiety-like behavior of rats exposed to SPS through MeCP2 and the subsequent upregulation of BDNF levels. Then tropomyosin-related kinase B (TrkB) and downstream signals, including MAP kinase ERK1/2 and phosphoinositol 3-kinase (PI3K)/Akt pathways, were activated by BDNF upregulation, and might participate in regulating dendritic complexity and the expression of postsynaptic density-95 (PSD95) and synapsin I in the PFC of SPS rats. Furthermore, we found that the apoptosis of cells in PFC induced by SPS procedure could be alleviated by miR-132 inhibition. Our results suggest that miR-132 might be involved in the formation of anxiety-like symptoms of adult rat PTSD models by targeting MeCP2, and this effect is related to BDNF/TrkB and its downstream ERK and Akt signaling pathways.
创伤后应激障碍（PTSD）通常伴有焦虑症状，且脑源性神经营养因子（BDNF）表达降低，而BDNF在促进神经元增殖和存活中起重要作用。甲基CpG结合蛋白2（MeCP2）是BDNF的正向调节因子，受miR-132-3p调控。在本研究中，我们探讨了miR-132可能的分子机制，重点关注MeCP2和BDNF在PTSD焦虑样症状形成中的作用。采用单次长时间应激（SPS）建立成年大鼠PTSD模型，通过高架十字迷宫（EPM）测试焦虑样行为。前额叶皮质（PFC）中miR-132水平升高，脑室内注射抗miR-132可通过MeCP2及随后BDNF水平的上调显著改善暴露于SPS的大鼠的焦虑样行为。然后，BDNF上调激活了原肌球蛋白相关激酶B（TrkB）及其下游信号，包括丝裂原活化蛋白激酶ERK1/2和磷脂酰肌醇3激酶（PI3K）/Akt通路，这些信号可能参与调节SPS大鼠PFC中树突复杂性、突触后致密蛋白95（PSD95）和突触素I的表达。此外，我们发现抑制miR-132可减轻SPS诱导的PFC细胞凋亡。我们的结果表明，miR-132可能通过靶向MeCP2参与成年大鼠PTSD模型焦虑样症状的形成，且这种作用与BDNF/TrkB及其下游ERK和Akt信号通路有关。
