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2016年7月15日讯 /生物谷BIOON/ –最近来自西南医学中心的科学家们在大脑中找到了一个可能导致抑郁的蛋白，他们利用基因疗法对这个新靶点进行了干预，发现小鼠的抑郁症行为得到了改善。该研究将促进抑郁症新治疗方法的开发。
研究人员发现一类叫做HCN的通道蛋白减少会抑制小鼠的抑郁症类似行为。如果该结果可以复制到人类，将为几百万对现有治疗方法无应答的抑郁症患者提供新疗法。
该研究结果发表在国际学术期刊Molecular Psychiatry上。
目前绝大多数抗抑郁症药物都会通过增加单胺类神经递质如5-羟色胺、多巴胺和去甲肾上腺素来影响病人心情和情绪，但是事实上这些药物对许多病人并不有效，这表明还有其他导致抑郁症的机制并没有被发现，而这些未发现机制将有可能为新治疗方法开发提供靶点。
在这项研究中，研究人员将一种能够关闭HCN通道的基因添加到工程改造的病毒中，随后通过注射的方法将病毒注射到小鼠的海马神经元。当HCN通道的功能被关闭，小鼠的行为就像接受了抗抑郁症药物的治疗一样。而重新增强HCN通道蛋白的功能则会抵消病毒的抗抑郁效果。
为了衡量小鼠的抑郁症类似行为，科学家们检测了小鼠在完全放弃之前试图逃脱一个环境所需的时间，这种检测方法常用于制药行业进行抗抑郁小分子的筛选，目前市场上的药物就利用了这种筛选方法。
研究人员表示，这项工作发现了一个全新的抑郁症治疗靶点，未来他们打算利用这种基因治疗方法对病人进行治疗。（基因宝jiyinbao.com）
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HCN-channel dendritic targeting requires bipartite interaction with TRIP8b and regulates antidepressant-like behavioral effects
Y Han, R J Heuermann, K A Lyman, D Fisher, Q-A Ismail and D M Chetkovich
Major depressive disorder (MDD) is a prevalent psychiatric condition with limited therapeutic options beyond monoaminergic therapies. Although effective in some individuals, many patients fail to respond adequately to existing treatments, and new pharmacologic targets are needed. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate excitability in neurons, and blocking HCN channel function has been proposed as a novel antidepressant strategy. However, systemic blockade of HCN channels produces cardiac effects that limit this approach. Knockout (KO) of the brain-specific HCN-channel auxiliary subunit tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) also produces antidepressant-like behavioral effects and suggests that inhibiting TRIP8b function could produce antidepressant-like effects without affecting the heart. We examined the structural basis of TRIP8b-mediated HCN-channel trafficking and its relationship with antidepressant-like behavior using a viral rescue approach in TRIP8b KO mice. We found that restoring TRIP8b to the hippocampus was sufficient to reverse the impaired HCN-channel trafficking and antidepressant-like behavioral effects caused by TRIP8b KO. Moreover, we found that hippocampal expression of a mutated version of TRIP8b further impaired HCN-channel trafficking and increased the antidepressant-like behavioral phenotype of TRIP8b KO mice. Thus, modulating the TRIP8b–HCN interaction bidirectionally influences channel trafficking and antidepressant-like behavior. Overall, our work suggests that small-molecule inhibitors of the interaction between TRIP8b and HCN should produce antidepressant-like behaviors and could represent a new paradigm for the treatment of MDD.