Metabotropic glutamate receptor-mediated synaptic plasticity in the basal ganglia

基底神经节代谢型谷氨酸受体介导的突触可塑性

• 批准号: 7909971
• 负责人: Kari Johnson
• 金额: $ 2.57万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7909971
• 关键词: Acute; Agonist; Basal Ganglia; Brain; Cells; Disease; Dopamine; Drug Delivery Systems; Event; Excitatory Synapse; G-Protein-Coupled Receptors; Knockout Mice; Lead; Long-Term Depression; Long-Term Effects; Measures; Mediating; Metabotropic Glutamate Receptors; Motor; Movement; Movement Disorders; Neurons; Output; Parkinson Disease; Pathogenesis; Patients; Pharmacological Treatment; Play; Quality of life; Role; Slice; Structure of subthalamic nucleus; Substantia nigra structure; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Testing; Therapeutic; improved; interest; metabotropic glutamate receptor 2; metabotropic glutamate receptor 3; motor learning; novel; postsynaptic; public health relevance; tool; transmission process

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.

描述（由申请人提供）：基底神经节在控制自愿运动和运动学习中起着至关重要的作用。基底神经节功能的破坏会导致诸如帕金森氏病（PD）等毁灭性运动障碍。为了发现针对PD等疾病的新疗法，强烈的努力集中在理解正常和病理状态的基底神经节的传播上（Delong和Wichmann，2007年）。代谢性谷氨酸受体（mglurs）是G蛋白偶联受体（GPCR），在整个基底神经节中广泛表达，并在基底神经节运动电路中的每个主要突触中调节突触传播（Conn等，2005，2005）。了解MGLUR在正常和疾病状态下基底神经节中的功能已导致鉴定出几种MGlur亚型，这些亚型可能为PD的药理治疗提供了有希望的靶标。我们对II组MGLURS（MGLUR2和MGLUR3）在亚丘脑下核（STN）和黑质Nigra pars niticulata（SNR）之间的作用特别感兴趣。 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，并且在PD患者中过度活跃。 II组mglurs调节STN-SNR突触兴奋性传播的急性和长期抑郁（LTD）（Bradley等，2000； Wittmann等，2002）。对于拟议的研究，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以及MGLUR2和-3基因敲除小鼠来确定哪种II组MGlur亚型介导了II组MGLUR激动剂对兴奋性传播的急性和长期影响。此外，我还将表征LTD诱导涉及的突触事件，以增强人们对这种新型突触可塑性形式的机制的了解。最后，我将测试多巴胺耗竭的作用，以了解如何在PD等病理状态中改变MGLUR功能。了解多巴胺如何调节MGLUR功能对于针对MGLURS治疗PD的药物的治疗潜力以及MGLUR功能的变化如何有助于PD症状的发病机理。 公共卫生相关性：对基底神经节中代谢剂谷氨酸受体功能的功能的研究可能会导致人们对基底神经节功能变化的了解，从而导致帕金森氏病的运动症状。这些研究的结果还可能导致治疗治疗帕金森氏病的毁灭性症状的治疗方法，这可能会增加许多患者的生活质量。