Beta-catenin modulates dopamine dependent signal transduction and behavior.

描述（由申请人提供）：基底神经节是大脑中无数过程的关键调节器，包括运动控制和行为。该系统根据解剖位置和连接性分为几个核，其中最大的称为纹状体。纹状体的主要神经元细胞类型是抑制性中型棘神经元（MSN），其基于解剖学和生物化学的功能差异形成直接和间接通路。生物化学上，两种MSN种群都受来自中脑的多巴胺能神经元支配，并对单胺神经递质多巴胺作出反应。然而，多巴胺信号通过两个家族的G蛋白偶联受体（GPCR），称为D1和D2 GPCR，这是选择性地表达在MSN的直接或间接途径，分别。D1和D2 GPCR可以通过它们各自与下游第二信使cAMP的产生的正或负偶联而在生物化学上进一步区分。 多巴胺信号转导的干扰与许多精神健康障碍有关，包括焦虑症、精神分裂症、抑郁症和注意缺陷多动障碍。鉴于这些疾病在世界范围内的流行，研究，以阐明负责多巴胺信号转导的基本信号转导机制是必要的，以开发更有效的药物干预策略。最近的工作已经确定了一个G-蛋白的独立形式的多巴胺信号，调节行为。该途径依赖于2-抑制蛋白-2介导的AKT、GSK-32和蛋白磷酸酶2（PP 2A）的复合物形成。多巴胺刺激促进该复合物的形成，导致通过PP 2A抑制AKT而激活GSK-32，并激活多巴胺依赖性行为。目前，GSK-32在这种信号传导模式中的下游靶点尚未确定。临床有效的抗精神病药物靶向2-arrestin- 2介导的多巴胺信号传导的令人兴奋的发现为描绘该途径的下游效应物提供了进一步的理由。鉴于2-连环蛋白作为GSK-32作用的主要靶点的作用，以及许多报告表明2-连环蛋白可能是精神药物功效所必需的下游效应分子，我们建议测试多巴胺信号传导和精神药物的作用部分由2-连环蛋白介导的假设。该假设将通过询问两个具体目的来测试，所述两个具体目的利用全面的遗传分析来：1）表征高多巴胺能和低多巴胺能的小鼠模型中的2-连环蛋白信号传导，和2）确定2-连环蛋白信号传导在介导多巴胺依赖性信号传导中的必要性和使用2-连环蛋白的floxed等位基因的精神药物的作用，所述等位基因减弱或增强2-连环蛋白信号传导。该提案的完成将进一步深入了解多巴胺依赖性信号和行为。最终，这可能为开发更有效的神经系统疾病治疗方法提供一个框架。 公共卫生相关性：这项研究提案将为多巴胺信号转导机制提供新的见解。本研究的预期手稿将描述可用于神经系统疾病药物干预的新途径。基于这项工作的未来研究将提高受疾病影响的人的生活质量，并减少患者护理的经济负担。

DESCRIPTION (provided by applicant): The basal ganglia is a critical regulator of a myriad of processes in the brain including motor control and behavior. This system is divided into several nuclei based upon anatomical location and connectivity, the largest of which is referred to as the striatum. The predominant neuronal cell type of the striatum is the inhibitory medium spiny neuron (MSN), which form the direct and indirect pathway based upon functional differences in anatomy and biochemistry. Biochemically, both MSN populations are innervated by dopaminergic neurons from the midbrain and respond to the monoamine neurotransmitter dopamine. However, dopamine signals through two families of G-protein coupled receptors (GPCR)s referred to as D1 and D2 GPCRs, which are selectively expressed in MSNs of the direct or indirect pathway, respectively. D1 and D2 GPCRs can be further distinguished biochemically by their respective positive or negative coupling to the generation of the downstream second messenger cAMP. Perturbations to dopamine signal transduction are implicated in a number of mental health disorders including anxiety, schizophrenia, depression, and attention deficit hyperactivity disorder. Given the prevalence of these disorders world-wide, studies to elucidate the basic signal transduction mechanisms responsible for dopamine signal transduction are necessary to develop more effective strategies of pharmacological intervention. Recent work has identified a G-protein independent modality of dopamine signaling that regulates behavior. This pathway is dependent upon 2-arrestin-2 mediated complex formation of AKT, GSK-32, and protein phosphatase 2 (PP2A). Dopamine stimulus promotes formation of this complex, resulting in activation of GSK-32 through inhibition of AKT by PP2A, and activation of dopamine dependent behavior. Currently, downstream targets of GSK-32 in this signaling paradigm have not been identified. The exciting finding that clinically effective antipsychotics target 2-arrestin- 2 mediated dopamine signaling provides further justification for delineating the downstream effectors of this pathway. Given the role for 2-catenin as a primary target of GSK-32 action and numerous reports suggesting that 2-catenin may be a downstream effector molecule necessary for the efficacy of psychotropic drugs we propose to test the hypothesis that that dopamine signaling and the actions of psychotropic drugs are mediated in part by 2-catenin. This hypothesis will be tested by interrogation of two specific aims that utilize a comprehensive genetic analysis to: 1) Characterize 2-catenin signaling in mouse models of hyper- dopaminergia and hypo-dopaminergia and 2) Determine the necessity for 2-catenin signaling in mediating dopamine dependent signaling and the actions of psychotropic drugs using floxed alleles of 2-catenin, which attenuate or potentiate 2-catenin signaling. Completion of this proposal will provide further insight into dopamine dependent signaling and behaviors. Ultimately, this may provide a framework for the development of more efficacious treatments of neurological disease. PUBLIC HEALTH RELEVANCE: This research proposal will provide new insight into the mechanism of dopamine signal transduction. Anticipated manuscripts from this study will describe novel pathways that can be targeted for pharmacological intervention in neurological disease. Future studies based upon this work will improve the quality of life for those affected by disease and decrease the financial burden for patient care.