PV中间神经元介导的γ振荡神经微环路在氯胺酮抗抑郁中的作用及机制

项目名称： PV中间神经元介导的γ振荡神经微环路在氯胺酮抗抑郁中的作用及机制

项目编号： No.81503053

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 张广芬

作者单位： 中国人民解放军东部战区总医院

项目金额： 17.9万元

中文摘要： 抑郁症发病率高，现有治疗起效慢且有效率低。新近研究证实全麻药氯胺酮可快速、有效治疗抑郁症。我们前期研究发现微清蛋白（PV）中间神经元功能蛋白表达下调参与氯胺酮抗抑郁作用，但具体机制尚待进一步探讨。鉴于①PV中间神经元是抑制性中间神经元，主要对锥体细胞提供抑制性信号；②PV中间神经元亦接受锥体细胞兴奋性信号传入，两者交互作用在γ振荡神经微环路的形成及调节中发挥重要作用；③γ振荡神经微环路异常与多种精神疾病密切相关，在抑郁症中其功能减弱。因此我们推测：PV中间神经元功能下调，对锥体细胞失去抑制，导致锥体细胞兴奋性及γ振荡神经微环路活动增强是氯胺酮抗抑郁的重要机制。本课题采用急慢性抑郁大鼠模型，通过行为学、分子生物学、电生理学等技术，从分子─细胞─神经微环路─整体水平等多层次研究PV中间神经元介导的γ振荡神经微环路在氯胺酮抗抑郁中的作用及机制，为寻找抗抑郁作用新靶点及研究抑郁发病机制提供新视角。

中文关键词： 氯胺酮；抗抑郁；中间神经元；γ振荡

英文摘要： Depression is a highly prevalent disorder and currently available antidepressant agents have delayed onset of actions and low remission rates. Recent studies have confirmed that ketamine, a general anesthetic, exerts rapid and robust antidepressant effects. Our previous studies suggest that the downregulation of functional proteins of parvalbumin (PV) interneurons is involved in the antidepressant effects of ketamine, however the exact mechanisms remain largely to be determined. Based on the following findings: ①PV interneurons are inhibitory interneurons, which mainly provide inhibitory signals to pyramidal cells; ②PV interneurons also accepted excitatory signals from pyramidal cells, and the interaction between the two kinds of cells plays an important role in the formation and regulation of the γ oscillation neural microcircuit; ③the abnormal γ oscillation neural microcircuit is deeply involved in the pathogenesis of many psychiatric disorders, and the function of γ oscillation neural microcircuit was decreased in the depression. Therefore, we hypothesized that the downregulation of PV function results in the disinhibition of pyramidal cells, subsequently increases the excitability of pyramidal cells and the activation of γ oscillation neural microcircuit, which is an important mechanism underlying ketamine's antidepressant effects. We will apply behavioral tests, molecular biotechnology, and electrophysiologic techniques to study the role of γ oscillation neural microcircuit mediated by parvalbumin interneurons in the antidepressant effects of ketamine and the underlying mechanism at molecular signaling, cell function, local neuronal circuits, and multiple aspects. This work will provide a new avenue for the investigation of new therapeutic target and pathogenesis of depression.

英文关键词： Ketamine;Antidepressant;Interneuron;Gamma oscillation