Beta-catenin modulates dopamine dependent signal transduction and behavior.

描述(申请人提供)：基底节是大脑中无数过程的关键调节器，包括运动控制和行为。根据解剖位置和连通性，这个系统被分成几个核，其中最大的被称为纹状体。纹状体的主要神经细胞类型是抑制性介质棘神经元(MSN)，根据解剖和生化功能的差异，形成直接和间接的通路。在生物化学方面，这两个MSN群体都受到来自中脑的多巴胺能神经元的神经支配，并对单胺类神经递质多巴胺做出反应。然而，多巴胺信号通过两个G蛋白偶联受体家族S称为D1GPCRs和D2GPCRs，它们分别选择性地表达在直接或间接途径的MSN中。D1GPCRs和D2GPCRs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来进一步在生化上加以区分。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、精神分裂症、抑郁和注意缺陷多动障碍。鉴于这些疾病在世界范围内的流行，研究阐明负责多巴胺信号转导的基本信号转导机制对于开发更有效的药物干预策略是必要的。最近的工作已经确定了一种不依赖于G蛋白的多巴胺信号模式，它可以调节行为。这一途径依赖于2-arrestin-2介导的AKT、GSK-32和蛋白磷酸酶2(PP2A)的复合体的形成。多巴胺刺激促进这种复合体的形成，通过PP2A抑制AKT而激活GSK-32，并激活多巴胺依赖的行为。目前，GSK-32在这一信号模式中的下游靶点尚未确定。临床上有效的抗精神病药物靶点2-arrestin-2介导的多巴胺信号转导的令人兴奋的发现为描述这一途径的下游效应提供了进一步的证据。鉴于2-连环蛋白作为GSK-32作用的主要靶点的作用，以及大量报道表明2-连环蛋白可能是精神药物疗效所必需的下游效应分子，我们建议检验以下假设：多巴胺信号和精神药物的作用部分由2-连环蛋白介导。这一假设将通过对两个特定目标的询问来验证，这两个目标利用全面的遗传分析来：1)在高多巴胺痛和低多巴胺痛小鼠模型中表征2-连环蛋白信号；2)确定2-连环蛋白信号在介导多巴胺依赖信号中的必要性，以及使用2-连环蛋白的花环等位基因来确定精神药物的作用，2-连环蛋白信号减弱或增强2-连环蛋白信号。这一提议的完成将进一步深入了解多巴胺依赖的信号和行为。最终，这可能会为开发更有效的神经疾病治疗方法提供一个框架。

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.