抑郁症侵蚀全球3.5亿人，传统药物起效慢，治愈率低。探讨抑郁症发病机制挖掘快速高效新靶点成为研究重点。我们前期研究发现抑郁模型CB1R功能失衡 (J PSYCHIATR RES, 2014)， 2-AG通过海马特异性LTD改善急性抑郁样行为（MOL PSYCHIATR，2016）后。新近发现：2-AG水解酶抑制剂JZL184快速缓解小鼠慢性抑郁行为，而GABA-AR激动剂可阻断其作用。已知抑郁模型去极化诱导的去抑制（DSI）效应减弱，JZL184诱导DSI对突触可塑性进行快速调节。那么，内源性大麻素2-AG是否通过DSI效应迅速调节突触可塑性产生快速抗抑郁作用呢？为验证该假说，本研究以细胞特异性CB1R基因敲除小鼠为平台，运用电生理、分子生物学及行为学等技术，系统分析2-AG快速抗抑郁作用并深入挖掘其机制。本研究的完成可进一步诠释抑郁症发病机制，也为临床快速抗抑郁药物研发提供可能的新靶点。

More than 350 million people are undergone major depressive disorder each year over the worldwide. However, conventional antidepressants have a low efficacy and a delayed onset of action.Thus, these have encouraged the search for new fast-act and long-lasting antidepressants. Recently, more data shows that endocannabinoid plays an important role in the pathophysiology of depression. After report of dysfunction of CB1R in depressive model (J PSYCHIATR RES, 2014) and the rapid antidepressant action of 2-AG on acute stress-exposed mice via glutamatergic synaptic long-term depression (LTD) (MOL PSYCHIATR，2016) , we recently found that JZL184 (MAGL inhibitor) can rapidly reverse the depressive behaviors (sucrose preference and immobility time in forced swimming test) in chronic depressive models. And mounting evidence shows the impaired DSI signaling in depressive model and JZL184 can produce rapid neuroplasticity by DSI, which is also verified by our data. So we hypothesize that the rapid antidepressant effect of JZL184 maybe induced by DSI action. The aim of current project is to explore the rapid antidepressant action of 2-AG and the possible underlying mechanisms by neuropharmacological and electrophysiological techniques as well as the transgenic animal models. The findings of current research will facilitate the understanding of depression and provide a new target for the development of new rapid antidepressants.