GABA-B RECEPTORS AND PARKINSON'S DISEASE

GABA-B 受体与帕金森病

• 批准号: 7715678
• 负责人: Yoland Smith
• 金额: $ 2.85万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7715678
• 关键词: Agonist; Animals; Basal Ganglia; Brain; Computer Retrieval of Information on Scientific Projects Database; Data; Depth; Dopamine; Electron Microscopy; Electrons; Funding; GABA transporter; Globus Pallidus; Goals; Grant; In Vitro; Institution; Mediating; Methods; Microscopic; Monkeys; Neurons; Parkinson Disease; Parkinsonian Disorders; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Rattus; Receptor Activation; Regulation; Relative (related person); Research; Research Personnel; Resolution; Resources; Role; Slice; Solid; Source; Synapses; Techniques; United States National Institutes of Health; awake; base; gamma-Aminobutyric Acid; in vivo; neurotransmitter release; patch clamp; presynaptic; receptor; receptor function; response; transmission process

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The main goals of this project are twofolds: (1) To characterize changes in the localization and function of GABAB receptors in MPTP-treated parkinsonian monkeys and (2) To elucidate the role of GABA transporters in the regulation of GABAB receptor activation in the globus pallidus. Over the past year, significant progress has been made towards the completion of these goals. First, using high resolution electron microscopy, we demonstrated a significant increase in the relative abundance of pre-synaptic GABAB receptors in the external and internal segments of the globus pallidus (GPe and GPi) in MPTP-treated parkinsonian monkeys. These findings suggest functional changes in GABAB-mediated presynaptic regulation of neurotransmitter release in the globus globus of parkinsonians. Second, we used in vivo electrophysiological recording technique in awake monkeys combined with local drug applications to study the effects of GABAB agonists and GABA transporter blockers on the physiological activity of GPe neurons in MPTP-treated monkeys. Although preliminary, data obtained so far suggest strong presynaptic effects of GABAB receptor activation on GABA release in the GPe of parkinsonian monkeys, while the blockade of GABA transporters in these dopamine-depleted animals elicit variable physiological responses, largely different from those recorded in normal monkeys. Finally, using in vitro patch clamp recording method in rat brain slices, we showed powerful effects of GABA transporter blockade on GABAB-mediated inhibitory transmission in rat GP neurons, suggesting the importance of non-synaptic GABA spillover in mediating GABAB receptors activation in the globus pallidus. These findings are consistent with our electron microscopic data showing that GABAB receptors are largely extrasynaptic in pallidal neurons. Together, these findings provide a solid basis for a deeper understanding of GABAB receptor function in the basal ganglia, and help characterize the potential significance of these receptors as new targets for drug therapy in Parkinson's disease.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 该项目的主要目标有两个：(1) 表征 MPTP 治疗的帕金森猴中 GABAB 受体定位和功能的变化；(2) 阐明 GABA 转运蛋白在调节球状球 GABAB 受体激活中的作用苍白球。过去一年，这些目标的实现取得了重大进展。首先，使用高分辨率电子显微镜，我们证明了 MPTP 治疗的帕金森猴苍白球外部和内部部分（GPe 和 GPi）突触前 GABAB 受体的相对丰度显着增加。 这些发现表明，帕金森病患者球状球中 GABAB 介导的突触前神经递质释放调节发生了功能变化。其次，我们利用清醒猴体内电生理记录技术结合局部药物应用，研究GABAB激动剂和GABA转运蛋白阻断剂对MPTP治疗猴GPe神经元生理活性的影响。尽管是初步的，但迄今为止获得的数据表明，GABAB 受体激活对帕金森猴 GPe 中 GABA 的释放具有强烈的突触前效应，而这些多巴胺耗尽的动物中 GABA 转运蛋白的阻断会引发不同的生理反应，与正常猴子中记录的生理反应有很大不同。 最后，在大鼠脑切片中使用体外膜片钳记录方法，我们显示了 GABA 转运蛋白阻断对大鼠 GP 神经元中 GABAB 介导的抑制性传递的强大影响，这表明非突触 GABA 溢出在介导球状球中 GABAB 受体激活中的重要性苍白球。这些发现与我们的电子显微镜数据一致，表明 GABAB 受体主要位于苍白球神经元的突触外。 总之，这些发现为更深入地了解基底神经节中 GABAB 受体的功能提供了坚实的基础，并有助于表征这些受体作为帕金森病药物治疗新靶点的潜在意义。