GABA-B RECEPTORS AND PARKINSON'S DISEASE

GABA-B 受体与帕金森病

• 批准号: 8172313
• 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: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172313
• 关键词: Affect; Antiparkinson Agents; Basal Ganglia; Brain; Complement; Complex; Computer Retrieval of Information on Scientific Projects Database; Corpus striatum structure; Development; Electrophysiology (science); Functional disorder; Funding; Future; GABA Transporter 1; GABA transporter; GABA-B Receptor; GAT3 transporter; Globus Pallidus; Goals; Grant; In Vitro; Institution; Mediating; Monkeys; Neurons; Parkinson Disease; Parkinsonian Disorders; Play; Procedures; Rattus; Receptor Activation; Research; Research Personnel; Resources; Role; Slice; Source; Synapses; Synaptic Transmission; United States National Institutes of Health; awake; gamma-Aminobutyric Acid; in vivo; local drug delivery; nonhuman primate; postsynaptic; presynaptic; receptor; research study; reuptake; 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 goal of this project is to characterize the anatomical and functional organization of basal ganglia GABA-B receptors in normal and parkinsonian conditions. During the past funding period, efforts have been devoted towards the understanding of the role GABA transporters (GATs) may play in regulating GABA-B receptors activation in the pallidal complex of normal and parkinsonian nonhuman primates. These experiments were complemented with in vitro electrophysiological studies in rat brain slices to further understand the synaptic mechanisms by which GAT blockade modulates activity of pre- and postsynaptic GABA-B receptors in the globus pallidus. The following conclusions can be made from these studies: (1) The subcellular localization of GATs in both the internal and external pallidal segments (GPi, GPe) is not affected in parkinsonian condition. Using in vivo electrophysiology recording procedures in awake monkeys combined with local drug delivery in GPe and GPi, we demonstrated that the effects of GAT-1 or GAT-3 blockade were similar to those seen in normal monkeys in the GPe, but unlike the findings in the normal state, the firing of most neurons was not affected by blockade of either transporter in GPi. These results suggest that, after dopaminergic depletion, the functions of GABA transporters are altered in GPi; without major changes in their subcellular localization. (2) Using in vitro slice electrophysiology, we have also demonstrated that both GABA transporters, GAT-1 and GAT-3, significantly regulate GABAA-receptor mediated GABAergic synaptic transmission in the rat GP, thereby providing evidence for the high expression level and functional importance of GATs in regulating GABAergic striatopallidal transmission. Knowing the importance of increased striatal GABAergic outflow to the GP in the pathophysiology of Parkinson's disease, GATs may be considered as potential targets for the future development of antiparkinsonian agents that could increase GAT-1- or GAT-3-mediated GABA reuptake functions in pathological conditions.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该项目的主要目的是表征正常和帕金森氏症状况下基底神经节GABA受体的解剖和功能组织。在过去的资金期间，努力旨在理解GABA转运蛋白（GAT）在调节正常和帕金森氏症非人类灵长类动物的苍白体复合物中的GABA-B受体激活方面发挥作用。这些实验与大鼠脑切片中的体外电生理研究相辅相成，以进一步了解GAT阻断调节球pallidus的突触前和突触后GABA-B受体的活性的突触机制。 从这些研究中可以得出以下结论：（1）在帕金森氏症情况下，内部和外部苍白球段（GPI，GPE）在内部和外部苍白球段（GPI，GPE）中的亚细胞定位均未影响。 Using in vivo electrophysiology recording procedures in awake monkeys combined with local drug delivery in GPe and GPi, we demonstrated that the effects of GAT-1 or GAT-3 blockade were similar to those seen in normal monkeys in the GPe, but unlike the findings in the normal state, the firing of most neurons was not affected by blockade of either transporter in GPi. 这些结果表明，在多巴胺能消耗后，GPI中GABA转运蛋白的功能发生了改变。没有重大变化的亚细胞定位。 （2）使用体外切片电生理学，我们还证明了GABA转运蛋白GAT-1和GAT-3都显着调节了大鼠GP中GABAA受体受体介导的GABAergic Synaptic Transpormation，从而提供了GAT在调节Gabaergriat striat striatal striatal striatal striatal striatal striatal striatal striatal striatal striatal striatal striatal striatal striat palliatal striat palliat palliat palliatial palliatialiD的证据。知道帕金森氏病的病理生理学中纹状体GABA能流出对GP的重要性，GAT可能被认为是抗帕金森氏病毒未来发展的潜在靶标，这些靶标可能会在病理条件下增加GAT-1-或GAT-3介导的GABA介导的GABA重摄取功能。