Up-regulation of SIRT6 in the hippocampus induced rats with depression-like behavior via the block Akt/GSK3β signaling pathway

• Published in: Behavioural brain research 2017-04, Vol.323, p.38-46
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Akt-GSK3β; Animals; Chronic unpredicted mild stress; CUMS; Depression; Depressive Disorder, Major - metabolism; Glycogen Synthase Kinase 3 beta - metabolism; Hippocampus; Hippocampus - metabolism; Lentivirus; Male; Neuron; Neuronal Plasticity; Neurons - metabolism; Proteomics; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Sprague-Dawley; RNA, Messenger - metabolism; Signal Transduction; Signaling pathway; SIRT6; Sirtuins - metabolism; Stress, Psychological - metabolism; Up-Regulation
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2017.01.035

•Ingenuity Pathway Analysis assessed networks in a rat model of depression (CUMS).•Up-regulation of SIRT6 in the hippocampus of CUMS rat is associated with depression-like behavior.•SIRT6 effects the survival and synaptic plasticity of hippocampal neuron via inhibitory activation of Akt-GSK3β signaling pathway. 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.