双孔钾离子通道TREK-1是位于细胞膜上的背景钾离子通道，参与调节静息膜兴奋性。最近有研究提出TREK-1通道与抗抑郁剂作用机制相关，TREK-1拮抗剂可能具有潜在的抗抑郁效应，但是其确切的信号转导机制尚未明了。本研究拟在前期工作基础上，应用CUMS拟抑郁样小鼠模型评估局部脑区TREK-1基因沉默或过表达对抑郁表型、神经递质释放以及海马神经再生的影响，阐明TREK-1通道对前额皮层和海马神经元树突形态、突触结构和突触传递功能的影响，及其与mTOR信号转导通路的可能关系，揭示TREK-1通道对突触发生的调节作用以及与抑郁症发生发展的相关性。研究成果不仅有助于深化对抑郁症病理机制的认识，也为寻找抑郁症更为有效的治疗措施提供新的实验依据。

The two-pore domain potassium channel TREK-1 is a member of background (also called baseline or leak) K+ channels that are thought to provide baseline regulation of membrane excitability. Recent studies have highlighted the putative role of the TREK-1 channel in the action of antidepressants, and its antagonists might become effective antidepressants. However, the mechanisms underlying this action of TREK-1 have not been identified. In the present study, we intend to investigate the regulatory effects of TREK-1 knockdown or overexpression in specific brain regions on depressive phenotype, neurotransmitter release and neurogenesis in hippocampus with chronic mild unpredictable stress-induced anhedonia model of depression. The modulatory effect of TREK-1 on dendrite morphology, synaptic structure and synaptic transmission in prefrontal cortex or hippocampus, as well as the possible molecular mechanism related with mTOR signal transduction pathway, will also be investigated in the project. We propose that TREK-1 involves the pathogenesis of depression via regulating synaptogenesis. These findings will give us an insight into the pathological mechanism of depression and may improve the study of screening of new durg target for depression treatment.

2006年Heurteaux等报道双孔钾通道TREK-1在情绪调节中发挥重要作用，TREK-1基因敲除小鼠表现出抵抗抑郁表型；2010年Heurteaux等进一步发现Spadin(TREK-1通道阻滞剂)亚急性给药4d能够改善小鼠抑郁样行为，提示TREK-1可能是研发快速抗抑郁治疗药物的重要靶标。我们的研究发现，研究组前期筛查的TREK-1拮抗剂SID1900能够快速改善CUMS大鼠抑郁样行为，但其确切分子机制尚不清楚。TREK-1是否参与调节突触发生及抑郁样行为，以及TREK-1拮抗剂SID1900的抗抑郁治疗机制，是本课题关注的焦点，围绕关键科学问题，我们开展了系列研究，取得了一些有价值的研究发现和成果。首先发现TREK-1与原代培养的海马神经元突触发生关系密切，可能是糖皮质激素抑制神经元突触发生的重要调控靶点。其次，海马脑区TREK-1基因沉默可减轻应激小鼠的抑郁样行为，海马脑区过表达TREK-1基因可加重应激小鼠的抑郁样行为。另外，TREK-1表达增高与抑郁模型小鼠的抑郁样行为、皮层和海马的神经元突触发生减低相关，TREK-1拮抗剂可部分逆转突触丢失。这些研究发现为深入探讨TREK-1功能及其可能的参与抗抑郁剂快速起效的分子机制打下了基础。