CDK5-mediated phosphorylation of Sirt2 contributes to depress

Activity-dependent viruses were used to selectively label and reactivate the subpopulation of neurons activated during SDS in VTA. (All viruses were packaged by BrainVTA)

The viruses used in this article from BrainVTA are in the table below

Activity-dependent	PT-0139 rAAV-cfos-tTA-WPRE-pA
	PT-0138 rAAV-TRE-tight-hM3D(Gq)-mCherry-WPRE-PA

Zheng Zhang, Pei Zhang, Guang-Jian Qi, Feng-Juan Jiao, Qing-Zhi Wang, Jian-Guo Yan, Feng He, Qian Zhang, Ze-Xi Lv, Xiang Peng, Hong-Wei Cai, Xiaoqian Chen, Ning Sun, Bo Tian
Pub Date: 2017-11-20, DOI: 10.1016/j.bbadis.2017.11.012, Email: sales@brainvta.com
Major depressive disorder (MDD) is a common, severe and recurrent psychiatric disorder worldwide; however, the underlying neuropathological mechanisms remain elusive. Histone deacetylases (HDACs) appear to play an essential role in depression. As the class III HDACs, Sirt1 and Sirt2 have attracted the most interest in the nervous system. Indeed, chronic stress decreased Sirt1 activity and down-regulated Sirt1 gene expression in MDD. Nevertheless, there is a paucity of literature on the role of Sirt2. To study the role of Sirt2 we established a MDD mouse model in wild type and Sirt2 knockout C57BL/6 mice using social defeat stress (SDS). We found that a lack of Sirt2 blocked the development of SDS-induced depressive-like behavior. Moreover, SDS led to Sirt2 phosphorylation in the amygdala without changing total Sirt2 levels, and blocking the phosphorylation of Sirt2 by CDK5 at serine residues 368 and 372 prevented SDS-induced depressive-like behavior and Sirt2 nuclear import. We also discovered that SDS-induced Sirt2 phosphorylation was involved in VTA-amygdala modulation using TetTag-pharmacogenetic method. These results suggest that CDK5 mediates phosphorylation of Sirt2 in the amygdala and contributes to the depressive-like behavior induced by SDS. This study highlights that inhibiting CDK5-dependent phosphorylation of Sirt2 at serine residues 368 and 372 by myristoylated membrane-permeabilising peptide (Sirt2-p), rather than using non-specific sirtuin inhibitors, may be a novel strategy for treating depression.

Figure 1. Selective labelling of Gq-DREADD in ventral tegmental area (VTA) neurons activated during SDS.

This study is aimed to explore the underlying neuropathological mechanisms on major depressive disorder (MDD). Their results suggest that CDK5 mediates phosphorylation of Sirt2 in the amygdala and contributes to the depressive-like behavior induced by SDS.

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