GABA-B RECEPTORS AND PARKINSON'S DISEASE

GABA-B 受体与帕金森病

• 批准号: 7958115
• 负责人: Yoland Smith
• 金额: $ 4.39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7958115
• 关键词: Agonist; Basal Ganglia; Brain; Cells; Computer Retrieval of Information on Scientific Projects Database; Disease; Funding; GABA transporter; GABA-B Receptor; GAT3 transporter; Globus Pallidus; Goals; Grant; Injection of therapeutic agent; Institution; Mediating; Methods; Monkeys; Neurons; Parkinson Disease; Parkinsonian Disorders; Presynaptic Receptors; Primates; Rattus; Receptor Activation; Regulation; Research; Research Personnel; Resources; Role; Slice; Solid; Source; Testing; United States National Institutes of Health; base; gamma-Aminobutyric Acid; new therapeutic target; patch clamp; 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: (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 (GP). Over the past year, two monkeys were rendered parkinsonian with weekly injections of MPTP. We then studied the activity of single neurons in GPe, before, during and after local injection of GABA-B receptor agonist and antagonist or GAT-1 or GAT-3 blockers. The effects of the GABA-B agonist were similar to what we found previously in normal monkeys, that is, a profound decrease in the firing of all GPe neurons tested. In contrast, blockade of GABA-B receptors induced variable responses, most noticeable an increase in firing. A possible way to interpret this unexpected result is that the GABA-B presynaptic receptors are upregulated in parkinsonism so that their blockade produced an increased GABAergic transmission, and a subsequent decrease in firing. The effects obtained with the GATs blockers were different from those observed in normal monkeys, ie both GAT-1 and GAT-3 blockade produced consistent decrease in the cell firing in normal monkeys, while there was often no effect on the firing rate of GPe cells after blockade of GAT-1 and even less after GAT-3 transporter blockade in parkinsonians. Finally, using patch clamp recording method in brain slices, we showed powerful effects of GABA transporter blockade on GABAB-mediated transmission in rat GP neurons, suggesting the importance of non-synaptic GABA spillover in mediating GABAB receptors activation in the GP. 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 therapeutic targets for 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。 该项目的主要目标是：(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 转运蛋白在苍白球 GABAB 受体激活调节中的作用（全科医生）。 在过去的一年里，两只猴子因每周注射 MPTP 而患上帕金森病。然后，我们研究了局部注射 GABA-B 受体激动剂和拮抗剂或 GAT-1 或 GAT-3 阻断剂之前、期间和之后 GPe 中单个神经元的活性。 GABA-B 激动剂的效果与我们之前在正常猴子中发现的效果相似，即所有测试的 GPe 神经元的放电都显着减少。相比之下，GABA-B 受体的阻断会引起不同的反应，最明显的是放电的增加。解释这一意外结果的一种可能方法是，GABA-B 突触前受体在帕金森病中上调，因此它们的阻断产生了 GABA 能传递的增加，以及随后放电的减少。使用 GAT 阻断剂获得的效果与在正常猴子中观察到的效果不同，即 GAT-1 和 GAT-3 阻断均导致正常猴子的细胞放电持续减少，而对 GPe 细胞的放电率通常没有影响帕金森病患者在阻断 GAT-1 后，甚至在阻断 GAT-3 转运蛋白后更少。最后，在脑切片中使用膜片钳记录方法，我们显示了 GABA 转运蛋白阻断对大鼠 GP 神经元中 GABAB 介导的传输的强大影响，表明非突触 GABA 溢出在介导 GP 中 GABAB 受体激活中的重要性。 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新治疗靶点的潜在意义。