Mao Qiang, Gong Xue, Zhou Chanjuan, Tu Zhe, Zhao Libo, Wang Ling, Wang Xinfa, Sun Lu, Xia Jinjun, Lian Bin, Chen Jianjun, Mu Jun, Yang Deyu, Xie Peng
Department of Neurology, Yongchuan Hospital, Chongqing Medical University, Chongqing 402460, China; Department of Neurology, the First Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China; Department of Neurology, The Fifth People's Hospital of Chongqing, Chongqing 400016, China.
Department of Neurology, Yongchuan Hospital, Chongqing Medical University, Chongqing 402460, China; Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing 400016, China; Department of Neurology, The Fifth People's Hospital of Chongqing, Chongqing 400016, China.
Behav Brain Res. 2017 Apr 14;323:38-46. doi: 10.1016/j.bbr.2017.01.035. Epub 2017 Jan 24.
Major depression is the leading cause of disability worldwide, which is associated with diverse alterations in brain such as neuro-inflammation, synaptic dysfunction, and cognitive deficit. Accumulating evidences suggest sirtuins (SIRTs) are involved in brain developmental disorders, metabolic diseases and play a key role in cognition and synaptic plasticity, yet the role in mood regulation remains controversial. Hence, Western blotting and RT-qPCR were used to investigate whether SIRTs (SIRT1-7) expression levels were altered in the hippocampus of rats, which followed 5 weeks of chronic unpredictable mild stress (CUMS) treatment, the results showed depressive-like behaviors: like body weight, forced swim test and sucrose preference test and SIRT6 was a significant increase in the hippocampal of CUMS rats. Furthermore, via a lentivirus-mediated transfection in hippocampal neurons, we aimed to detect how SIRT6 influence the function of hippocampus. The SIRT6 overexpression significantly inhibited expressions of proteins and/or phosphoproteins (e.g AKT, p-AKT, P-GSK3β), decreased the ratios of p-GSK3β/GSK3β and p-Akt/Akt in the primary hippocampus neurons. Thus, our data indicates that SIRT6 is involved in the modulation of depressive-like behaviors and affects the survival and synaptic plasticity of hippocampal neuron via inhibitory activation of Akt-GSK3β signaling.
重度抑郁症是全球致残的主要原因，它与大脑中的多种改变有关，如神经炎症、突触功能障碍和认知缺陷。越来越多的证据表明，沉默调节蛋白（SIRTs）与脑发育障碍、代谢疾病有关，并且在认知和突触可塑性中起关键作用，但其在情绪调节中的作用仍存在争议。因此，我们使用蛋白质免疫印迹法和逆转录定量聚合酶链反应来研究在经历5周慢性不可预测轻度应激（CUMS）处理后大鼠海马体中沉默调节蛋白（SIRT1-7）的表达水平是否发生改变，结果显示出现了类似抑郁的行为，如体重、强迫游泳试验和蔗糖偏好试验，并且在CUMS大鼠的海马体中SIRT6显著增加。此外，通过慢病毒介导的海马神经元转染，我们旨在检测SIRT6如何影响海马体的功能。SIRT6过表达显著抑制了蛋白质和/或磷酸化蛋白（如AKT、p-AKT、P-GSK3β）的表达，降低了原代海马神经元中p-GSK3β/GSK3β和p-Akt/Akt的比值。因此，我们的数据表明，SIRT6参与了类似抑郁行为的调节，并通过抑制Akt-GSK3β信号通路的激活影响海马神经元的存活和突触可塑性。
