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: 8258278
• 负责人: Kari Johnson
• 金额: $ 1.17万
• 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/8258278
• 关键词: Acute; Address; Agonist; Amygdaloid structure; Animal Model; Animals; Antiparkinson Agents; Basal Ganglia; Brain; Brain region; Cell Nucleus; Cells; Data; Disease; Dopamine; Dopamine D1 Receptor; Drug Delivery Systems; Dystonia; Event; Excitatory Synapse; G-Protein-Coupled Receptors; Huntington Disease; Knockout Mice; Lead; Long-Term Depression; Long-Term Effects; Measures; Medial; Mediating; Metabotropic Glutamate Receptors; Motor; Movement; Movement Disorders; N-Methyl-D-Aspartate Receptors; Neurons; Nucleus Accumbens; Output; Parkinson Disease; Pathogenesis; Patients; Pharmacological Treatment; Play; Prefrontal Cortex; Quality of life; Rattus; Receptor Activation; Relative (related person); Reporting; Reserpine; Role; Slice; Structure of subthalamic nucleus; Structure of terminal stria nuclei of preoptic region; Substantia nigra structure; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Testing; Therapeutic; improved; interest; metabotropic glutamate receptor 2; metabotropic glutamate receptor 3; motor learning; neurotransmission; novel; patch clamp; postsynaptic; presynaptic; receptor; response; tool; transmission process

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.

基底神经节在控制随意运动和运动学习中发挥着关键作用。基底神经节功能的破坏会导致毁灭性的运动障碍，例如帕金森病 (PD)。为了发现帕金森病等疾病的新疗法，人们一直致力于了解正常和病理状态下基底神经节的传播（DeLong 和 Wichmann，2007）。代谢型谷氨酸受体 (mGluR) 是 G 蛋白偶联受体 (GPCR)，在整个基底神经节中广泛表达，并调节基底神经节运动回路内每个主要突触的突触传递 (Conn et al., 2005)。了解正常和疾病状态下基底神经节中 mGluR 的功能已导致鉴定出几种 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 mGluR（mGluR2 和 mGluR3）在丘脑底核 (STN) 和黑质网状部 (SNr) 之间突触的作用特别感兴趣。 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发挥关键作用，并且在 PD 患者中过度活跃。 II 组 mGluR 调节 STN-SNr 突触兴奋性传递的急性和长期抑制 (LTD)（Bradley 等人，2000 年；Wittmann 等人，2002 年）。对于拟议的研究，我将使用全细胞电生理学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 敲除小鼠来确定 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LTD诱导过程中涉及的突触事件的特征，以便更好地理解这种新型突触可塑性背后的机制。最后，我将测试多巴胺耗竭的影响，以了解 mGluR 功能在 PD 等病理状态下如何改变。了解多巴胺如何调节 mGluR 功能对于靶向 mGluR 的药物治疗 PD 的治疗潜力以及 mGluR 功能的变化如何促进 PD 症状的发病机制非常重要。