受体别构调节是有别于正位配体(ligand)的受体功能调控机制，由于其作用上具有时间和空间选择性因而较之传统的正位配体在安全性和选择上有较大优势。Sigma-1受体既具受体活性又有分子伴侣功能，其生物学功能因此较为复杂。以Sigma-1受体为靶向的抗抑郁研究虽较为活跃,但传统的正位激动剂因为潜在严重副作用而受到限制。我们近来发现别构调节sigma-1受体可产生快速抗抑郁作用，并首次发现sigma-1受体与BDNF存在一个环路调节现象。本项目以此为基础，深入研究sigma-1受体与抑郁症发生发展的分子机制及sigma-1受体别构调节抗抑郁作用，并以具有自我知识产权的国际上首个高选择性、高效sigma-1受体别构调节剂SOMCL-668为手段，对sigma-1受体别构调节抗抑郁作用及机理进行系统研究，为基于sigma-1受体别构调节的抗抑郁药物发现提供新靶点、新策略。

Allosteric regulating receptor is an important modulatory mechanism for receptor function.Compared to receptor orthodox ligand, allosteric receptor modulation has tramadous advantage in term of the safety and less adverse effects as drug. Sigma-1 receptor, distributed in CNS, functions as a receptor and chaperon protein, which renders the receptor a complex functions.The antidepression of sigma-1 receptor agonist is actively studied, however, the application of such kind of drug is limited because of the safety concern. We recently discovered a new and potent, with high selectivity, sigma-1 receptor allosteric modulator SOMCL-668, and found SOMCL-668 produced a rapidly antidepressant effects which appears to be associated with production of BDNF in hipocampus. We further found that the effects of BDNF on ERK activation and inhibition of GSK-3β in cutured neurons were dramatically attenuated in the presence of sigma-1 receptor antagonist or in sigma-1 receptor knockdown cells, so was the DNDF-stimulated neurite outgrowth. Indicating that the function of BDNF is dependent on sigma-1 receptor. In the present proposal, we will take the advantage of nearly discovered sigma-1 receptor allosteric modulator SOMCL-668 and investigate the effects of sigma-1 receptor allosteric regulation in the depression and its underlined mechanisms. There are three specific aims: 1. To investigate the effects of chronic SOMCL-668 treatment on dendritic morphology and neurogenesis in either wt or sigma-1 receptor knockout mice; 2. To investigate the signaling mechanism and molecular events between signa-1 receptor and BDNF functional and physical couplings; 3. The electricphysiological studies on sigma-1 - modulated hippocampal functions; This work will provide novel insight on role of sigma-1 receptor in depression and potential new target (allosteric sigma-1 receptor modulation)for antidepressant drug discovery.