Sirt1/PGC-1α介导PV阳性GABA能中间神经元的功能异常促进抑郁症发生

临床研究显示Sirt1基因多态性与抑郁症的发生相关，但机制尚不明确。抑郁症患者的尸检及我们前期在抑郁症小鼠模型中，均发现前额叶皮质和海马内PV阳性GABA能中间神经元的数量减少。有研究表明PGC-1α在调控PV阳性GABA能中间神经元的功能中发挥重要作用，但Sirt1/PGC-1α在抑郁症发生中的作用及机制鲜见报道。本研究以慢性不可预见性温和刺激诱导PV-ires-Cre小鼠、SIRT1KI或SIRT1co/ co与PV ires-Cre 杂交小鼠，并通过病毒介导调控PGC-1α的表达，借助光遗传学、行为学、脑片电生理及分子生物学等方法，揭示应激可通过SIRT1下调PGC-1α影响神经环路中PV阳性GABA能神经元的功能，从而导致抑郁症的发生。本项目有助于深入理解环境应激和遗传因素导致抑郁症发生的分子机制，也为抗抑郁药的研发提供理论依据和新的靶点。

Clinical studies have shown the SIRT1 polymorphisms is associated with Major Depression Disorder (MDD), but the mechanism is unclear. The loss of PV-positive GABAergic interneuron in mPFC and Hippocampus is appeared in the autopsy for MDD and in the depression model mice. Previous studied have verified that PGC-1α play an important role in regulating the PV interneuron, however, it remains unclear about the role and mechanism of Sirt1/ PGC-1α affecting MDD. In present study, the chronic unpredicted mild stress (CUMS) is used to establish the mice depression model. The expression of PGC-1α or Sirt1 within PV interneuron is targeted regulation via injecting AAV or breeding the SIRT1KI or SIRT1co/ co lien mice and PV ires-Cre line mice respectively. A variety of methods, such as optogenetics, behaviors, slice electrophysiology will be used in the study. These studies will reveal that chronic stress-mediated decline of PGC-1α, presumably mediated by low activation of Sirt1, results in dysfunction of PV-positive GABAergic interneuron, which, in turn, might contribute the depressive-like behavior. This study will help to investigate the mechanism that environmental stress and genetic factors contribute to depression, and provide new targets for antidepressant drug development.