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，治疗仅在一定比例的人群中有效。抗抑郁药物，包括选择性5-羟色胺再摄取抑制剂（SSRIs），是最常用的抗抑郁药物，在抑郁症动物模型中有效。SSRI通过5 HT受体间接起作用，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（Regulators of G protein signaling，RGS）是一类负性调节受体介导的G蛋白信号转导的细胞内蛋白。使用突变小鼠表达的RGS不敏感的G？i2蛋白，我们已经确定了介导抗抑郁和抗焦虑行为的5 HT 1A受体下游的通路。这使我们认为RGS蛋白对5 HT 1A受体信号的调节可能在抑郁症中起重要作用，因此为抑郁症的治疗提供了一个新的靶点。然而，存在>20种哺乳动物RGS蛋白，并且一般抑制剂将可能具有广泛的影响。在这项建议中，我们试图了解G的功能？通过识别负责观察到的表型的受体的位置，抗抑郁剂样作用的生化机制，以及涉及的特定RGS蛋白，在抑郁症动物模型中的i2-偶联5 HT 1A受体。拟议的工作将使用行为，生物化学和分子生物学方法相结合的转基因小鼠与基因敲入的RGS不敏感的G？i2蛋白，包括有条件的基因敲入动物，避免与代偿性变化相关的问题，并允许位点特异性表达的G？i2突变。这些研究将提供RGS蛋白在抑郁症动物模型中5-羟色胺信号传导的知识，并确定抗抑郁治疗的新靶点。特别地，RGS蛋白可以是直接的药物靶标和/或用于促进目前可用的SSRI的抗抑郁作用而不增强其不想要的作用。 抑郁症是一种人们知之甚少的疾病，影响着大约1000万美国人。此外，抑郁症的治疗对大多数患者无效。我们最近发现了一种转基因小鼠模型，该模型显示出抗抑郁样行为，并对选择性5-羟色胺再摄取抑制剂（SSRIs）反应良好。这些小鼠携带突变，使特定的细胞内信号蛋白（G蛋白）对其内源性调节因子（RGS蛋白）无反应。这种突变也增加了针对5-羟色胺5 HT 1A受体的药物的有效性，该受体与几种情绪障碍有关。在这项提案中，我们试图增加我们的理解5 HT 1A受体使用行为和生化措施，并确定特定的RGS蛋白（S）参与其调节。我们的目标是确定新的目标，为开发药物治疗抑郁症。

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.