Metabotropic glutamate receptor-mediated synaptic plasticity in the basal ganglia

描述（申请人提供）：基底神经节在控制自主运动和运动学习中起关键作用。基底神经节功能的破坏会导致严重的运动障碍，如帕金森病（PD）。为了发现PD等疾病的新治疗方法，人们一直致力于了解正常和病理状态下基底神经节中的传递（DeLong和Wichmann， 2007）。代谢型谷氨酸受体（mGluRs）是G蛋白偶联受体（gpcr），在基底神经节中广泛表达，并调节基底神经节运动回路中每个主要突触的突触传递（Conn et al., 2005）。了解mGluR在基底节区正常和疾病状态下的功能，可以确定几种mGluR亚型，这些亚型可能为PD的药物治疗提供有希望的靶点。我们对II组mGluRs （mGluR2和mGluR3）在丘脑底核（STN）和网状黑质（SNr）之间的突触中的作用特别感兴趣。STN-SNr突触是一种兴奋性突触，在调节基底神经节的信息输出中起关键作用，在PD患者中过度活跃。II组mGluRs调节STN-SNr突触兴奋性传递的急性和长期抑制（LTD） （Bradley et al. 2000; Wittmann et al. 2002）。对于提议的研究，我将使用全细胞电生理技术来测量急性脑切片中gaba能SNr神经元的兴奋性突触后电流。首先，我将使用我们最近开发的亚型选择性药理学工具和mGluR2和-3敲除小鼠来确定哪种II组mGluR亚型介导II组mGluR激动剂对兴奋性传递的急性和长期影响。此外，我将描述与LTD诱导有关的突触事件，以便更好地理解这种新形式的突触可塑性的机制。最后，我将测试多巴胺耗竭的影响，以了解mGluR功能如何在PD等病理状态下改变。了解多巴胺如何调节mGluR功能对于开发靶向mGluR治疗PD的药物的治疗潜力以及mGluR功能的改变如何参与PD症状的发病机制具有重要意义。

DESCRIPTION (provided by applicant): The basal ganglia play a critical role in controlling voluntary movement and motor learning. Disruption of basal ganglia function causes devastating movement disorders such as Parkinson's disease (PD). In order to discover novel treatments for disorders such as PD, intense effort has been focused on understanding transmission in the basal ganglia in both normal and pathological states (DeLong and Wichmann, 2007). Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors (GPCRs) that are widely expressed throughout the basal ganglia and modulate synaptic transmission at every major synapse within the basal ganglia motor circuit (Conn et al., 2005). Understanding the function of mGluRs in the basal ganglia in normal and disease states has led to identification of several mGluR subtypes that may provide promising targets for pharmacological treatment of PD. We are particularly interested in the role of group II mGluRs (mGluR2 and mGluR3) at the synapse between the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr). The STN-SNr synapse is an excitatory synapse that plays a key role in regulating information output from the basal ganglia and is overactive in PD patients. Group II mGluRs regulate both acute and long- term depression (LTD) of excitatory transmission at the STN-SNr synapse (Bradley et al. 2000; Wittmann et al. 2002). For the proposed studies, I will use whole-cell electrophysiological techniques to measure excitatory postsynaptic currents from GABAergic SNr neurons in acute brain slices. First, I will use subtype-selective pharmacological tools that we have recently developed and mGluR2 and -3 knockout mice to determine which group II mGluR subtype(s) mediates acute and long-term effects of group II mGluR agonists on excitatory transmission. In addition, I will characterize the synaptic events involved in the induction of LTD in order to gain an increased understanding of the mechanisms underlying this novel form of synaptic plasticity. Finally, I will test the effect of dopamine depletion in order to understand how mGluR function might be altered in pathological states such as PD. Understanding how dopamine modulates mGluR function is important for the therapeutic potential of drugs targeting mGluRs for treating PD, as well as how changes in mGluR function may contribute to the pathogenesis of PD symptoms. PUBLIC HEALTH RELEVANCE: Studies of the functions of metabotropic glutamate receptors in the basal ganglia may lead to an increased understanding of the changes in basal ganglia function that contribute to the motor symptoms of Parkinson's disease. The results of these studies may also lead to improved treatments for managing the devastating symptoms of Parkinson's disease, which could increase the quality of life for many patients.