GABAA RECEPTORS IN AGING

GABAA 受体在衰老过程中的作用

• 批准号: 2429296
• 负责人: ANGEL L DE BLAS
• 金额: $ 13.11万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-17 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2429296
• 关键词: GABA receptor; aging; autoradiography; cerebellar Purkinje cell; cerebellum; complementary DNA; growth factor receptors; hippocampus; immunocytochemistry; in situ hybridization; laboratory mouse; laboratory rat; messenger RNA; neuropharmacology; neurotrophic factors; northern blottings; nucleic acid probes; protein structure function; receptor binding; receptor expression; synapses; tissue /cell culture; western blottings

DESCRIPTION: (Applicant's abstract) This research is aimed at understanding the regulation of the GABAa receptor (GABAaR) expression in the hippocampus and cerebellum of the rat brain associated to normal aging. Approximately 30-40% of the brain synapses are GABAergic. Nevertheless, the role of GABA and GABAaR in aging has seldom been studied in spite of suggestive data indicating the existence of changes in GABA and GABAaR during normal aging. One of the main reasons for the scarcity of studies in this area has been the absence of appropriate tools other than specific receptor radioligands. The recent development in the applicants laboratory of monoclonal and polyclonal antibodies and cDNA probes for the different receptor subunits will allow them to approach the role of GABAaR in aging in a very effective way. The applicants have already provided evidence and studied the aging-related changes in some GABAaR subunits and GAD expression in some areas of the brain. The techniques involved are I) quantitative in situ, northern and dot blot hybridization for studying the mRNA expression of receptor subunits; II) quantitative immunocytochemistry, immunoblotting and immunoprecipitation for studying the protein expression; III) quantitative radioligand autoradiography for studying the ligand binding specificities of the receptor since it is expected that changes in receptor subunit composition leads to changes in binding affinities for some ligands. In addition, deafferentation models of the hippocampus and cerebellum will be used to test the hypothesis that some of the aging-related changes in GABAaR subunit expression are due to changes in neuronal connectivity. The possible involvement of neurotrophins and their receptors in the regulation of GABAaR subunit expression will also be investigated. These studies are directly relevant to aging in several ways: I) Much of the physical and mental deterioration associated with aging is due to impairments in brain physiology. Results obtained in our laboratory as well as in others indicate that the GABAaR change during aging. II) Memory, frequently is impaired during aging. Published results have shown the importance of the hippocampal GABAaR for the consolidation of memory. III) Benzodiazepines (ie. Librium and Valium) exert their action by binding to the GABAaR. Sleep disorders frequently accompany aging. Benzodiazepines are widely used to treat sleep disorders. IV) The GABAaR are also involved in the control of blood pressure and in areas of the brain involved in sensory-motor coordination, hearing and vision. In addition, the GABAaR are prominently involved in the physiology of the retina. Vision, hearing and motor coordination are frequently impaired during aging. V) Understanding of the aging-related changes in GABAaR subunit composition and ligand binding will help to develop drugs that would recognize specific types of GABAaR involved in an aging-related impaired function without affecting other GABAaR involved in other brain functions, thus eliminating most of the drug side-effects.

描述：（申请人的摘要）本研究旨在了解 海马 GABAa 受体 (GABAaR) 表达的调节 和与正常衰老相关的大鼠大脑小脑。 大约 30-40% 的大脑突触是 GABA 能的。 尽管如此，GABA 的作用 尽管有提示性数据，但 GABAaR 在衰老中的作用却很少被研究 表明正常衰老过程中GABA和GABAaR存在变化。 该领域研究稀缺的主要原因之一是 除特定受体放射性配体外，缺乏适当的工具。 申请人实验室单克隆抗体和单克隆抗体的最新进展 针对不同受体亚基的多克隆抗体和 cDNA 探针 将使他们能够非常有效地研究 GABAaR 在衰老中的作用 方式。 申请人已经提供了证据并研究了 一些 GABAaR 亚基的衰老相关变化和一些 GAD 的表达 大脑的区域。 所涉及的技术是 I) 原位定量， Northern 杂交和斑点印迹杂交用于研究 mRNA 表达 受体亚基； II) 定量免疫细胞化学、免疫印迹和 用于研究蛋白质表达的免疫沉淀；三）定量 放射性配体放射自显影用于研究配体结合特异性 受体，因为预计受体亚基的变化 组成会导致某些配体的结合亲和力发生变化。 在 此外，海马和小脑的传入神经阻滞模型将 用于检验 GABAaR 中一些与衰老相关的变化的假设 亚基表达是由于神经元连接的变化所致。 这 神经营养素及其受体可能参与调节 GABAaR 亚基表达的影响也将被研究。 这些研究在几个方面与衰老直接相关：I）大部分 与衰老相关的身体和精神退化是由于 大脑生理学损伤。 我们实验室也获得了结果 与其他研究一样，表明 GABAaR 在衰老过程中发生变化。 二）记忆， 在衰老过程中经常会受到损害。 公布的结果表明 海马 GABAaR 对于巩固记忆的重要性。 三） 苯二氮卓类药物（即利眠宁和安定）通过结合来发挥作用 GABAaR。 睡眠障碍常常伴随着衰老。 苯二氮卓类 广泛用于治疗睡眠障碍。 IV) GABAaR 也参与其中 控制血压和涉及大脑的区域 感觉运动协调、听觉和视觉。 此外，GABAaR 是 主要参与视网膜的生理学。 视力、听力和 在衰老过程中，运动协调性经常受到损害。 五）理解 GABAaR 亚基组成和配体与衰老相关的变化 结合将有助于开发能够识别特定类型的药物 GABAaR 参与与衰老相关的功能受损，但不影响 其他 GABAaR 参与其他大脑功能，从而消除了大部分 药物副作用。