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

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.

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。

抑郁症（Depression）是精神科常见疾病，以情绪低落、兴趣减退为核心症状，严重者可出现自杀观念和行为，其发病率高达17%，且呈上升趋势。近年来临床研究发现常用麻醉药氯胺酮可在数小时内产生显著的抗抑郁作用。目前，氯胺酮抗抑郁的作用机制尚不明确。本项目主要从微清蛋白（PV）中间神经元功能及兴奋/抑制平衡角度探讨氯胺酮抗抑郁的相关机制。.通过本项目研究，我们初步得出一些结果：.（1）在强迫游泳、LPS诱导的急性抑郁模型及CUMS诱导的慢性抑郁模型中，氯胺酮均可表现出显著的抗抑郁作用，并可导致皮层PV中间神经元PV表达及mRNA水平下调，而不影响SST中间神经元SST表达及mRNA水平。.（2）氯胺酮给药后大鼠前额皮层PV及GAD67蛋白表达下降，Glu含量增加，GABA含量下降。夹竹桃麻素及GABA预处理可阻断氯胺酮的抗抑郁作用。该部分结果提示PV中间神经元功能下调在氯胺酮抗抑郁中发挥重要作用，这可能与其介导的Glu信号系统去抑制有关。.（3）LPS可引起小鼠海马突触外CaMKIIα活性增加，GluN2B上膜，引发胞内钙离子过度内流，产生神经毒性，氯胺酮可逆转上述改变，从而发挥抗抑郁作用；氯胺酮可以快速恢复急性应激导致的脑区神经递质传递的失衡及海马突触可塑性损害，从而发挥抗抑郁作用。