Cellular Mechanisms in Animal Models of Depression

描述（由申请人提供）：抑郁症是一种人们知之甚少的疾病，治疗方法只对一定比例的人群有效。抗抑郁药物，包括选择性血清素再摄取抑制剂（SSRIs），是最常用的抗抑郁药物，对抑郁症动物模型有效。SSRI通过5HT受体间接作用，包括与异源三聚体G蛋白偶联的受体。G蛋白信号调节因子（regulatory of G protein signaling， RGS）是一个细胞内蛋白家族，可负调控受体介导的G蛋白信号。使用表达rgs不敏感的G？我们已经确定了5HT1A受体下游的途径，介导抗抑郁和抗焦虑行为。这使我们考虑到RGS蛋白对5HT1A受体信号的调节可能在抑郁症中发挥重要作用，因此为抑郁症的治疗提供了新的靶点。然而，哺乳动物的RGS蛋白有大约20种，一种普通的抑制剂可能会有广泛的作用。在这个提议中，我们试图理解G？i2偶联5HT1A受体在抑郁症动物模型中的作用，通过确定受体的位置，观察到的表型，抗抑郁样作用的生化机制，以及特定的RGS蛋白。拟议的工作将结合行为、生化和分子生物学方法，在基因修饰小鼠中敲入rgs不敏感的G？i2蛋白，包括条件敲入动物，避免与代偿性变化相关的问题，并允许位点特异性表达G？i2突变。这些研究将提供抑郁症动物模型中血清素信号中RGS蛋白的知识，并确定抗抑郁治疗的新靶点。特别是，RGS蛋白可能是直接的药物靶点和/或促进目前可用的SSRI的抗抑郁作用，而不会增强其不良影响。

DESCRIPTION (provided by applicant): Depression is an illness that is poorly understood and treatments are only effective in a certain percentage of the population. Antidepressant medications, including selective serotonin reuptake inhibitors (SSRIs), are the most prescribed antidepressant medications and are effective in animal models of depression. SSRI's act indirectly via 5HT receptors including receptors that couple to heterotrimeric G proteins. Regulators of G protein signaling (RGS) are a family of intracellular proteins that negatively modulate receptor-mediated G protein signaling. Using mutant mice expressing an RGS-insensitive G?i2 protein we have identified a pathway downstream of 5HT1A receptors that mediates antidepressant and anti-anxiety behaviors. This led us to consider that RGS protein modulation of 5HT1A receptor signaling may play an important role in depression and so present a novel target for the treatment of depression. However, there are >20 mammalian RGS proteins and a general inhibitor will likely have a broad range of effects. In this proposal we seek to understand the function of G?i2-coupled 5HT1A receptors in animal models of depression by identifying the location of receptors responsible for the observed phenotype, the biochemical mechanism underlying the antidepressant-like effect, and the particular RGS proteins involved. The proposed work will use a combination of behavioral, biochemical and molecular biological approaches in genetically modified mice with knock-in of RGS-insensitive G?i2 protein, including conditional knock-in animals that avoid problems associated with compensatory changes and allow for site-specific expression of the G?i2 mutation. These studies will provide knowledge of RGS proteins in serotonin signaling in animal models of depression and identify novel targets for antidepressant therapy. In particular, RGS proteins may be direct drug targets and/or act to promote the antidepressant actions of currently available SSRI's without enhancing their unwanted effects. PUBLIC HEALTH RELEVANCE: Depression is a poorly understood illness that affects approximately 10 million Americans. Moreover, treatments for depression are ineffective in a majority of patients. We have recently identified a transgenic mouse model that shows antidepressant-like behavior and responds very well to selective serotonin reuptake inhibitors (SSRIs). These mice carry a mutation that renders specific intracellular signaling proteins (G proteins) unresponsive to their endogenous regulators (RGS proteins). This mutation also increases the effectiveness of drugs targeting the serotonin 5HT1A receptor, a receptor that is linked to several mood disorders. In this proposal we seek to increase our understanding of 5HT1A receptors using behavioral and biochemical measures and identify the particular RGS protein(s) involved in their regulation. Our aim is to identify novel targets for the development of agents to treat depressive illness.