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）这项研究旨在理解 海马中GABAA受体（GABAAR）表达的调节 大鼠脑的小脑与正常衰老有关。 大约 30-40％的大脑突触是GABA能。 然而，加巴的角色 尽管有暗示性数据，但很少研究衰老的加巴尔 表明正常衰老期间GABA和GABAAR存在变化。 在这一领域缺乏研究的主要原因之一是 除特定受体放射性配体以外，没有适当的工具。 申请人单克隆实验室的最新发展和 不同受体亚基的多克隆抗体和cDNA探针 将使他们能够在非常有效的 方式。 申请人已经提供了证据，并研究了 某些GABAAR亚基的衰老相关变化和某些GAD表达 大脑区域。 所涉及的技术是i）定量原位， 北部和点印迹杂交用于研究的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； iii）定量 用于研究配体结合特异性的放射性自显影 受体由于受体亚基的变化是因为受体 组成会导致某些配体的结合亲和力变化。 在 此外，海马和小脑的剥离模型将是 用于测试Gabaar的某些与衰老相关的变化的假设 亚基表达是由于神经元连通性的变化所致。 这 神经营养蛋白及其受体可能参与调节 GABAAR亚基表达也将进行研究。 这些研究在几种方面与衰老直接相关：i）大部分 与衰老相关的身体和心理恶化是由于 大脑生理学障碍。 在我们的实验室也获得的结果 就像其他人一样，表明在衰老期间的Gabaar变化。 ii）记忆， 衰老期间经常会受到损害。 已发表的结果表明 海马Gabaar在巩固内存的重要性。 iii） 苯二氮卓类药物（即图书馆和Valium）通过与 加巴。 衰老经常伴随着睡眠障碍。 苯二氮卓 广泛用于治疗睡眠障碍。 iv）加巴也参与了 在控制血压和大脑的区域中 感觉运动协调，听力和视觉。 此外，加巴尔是 明显参与视网膜的生理学。 视觉，听力和 运动配位在老化期间经常受到损害。 v）理解 GABAAR亚基组成和配体的衰老相关变化 约束将有助于开发可以识别特定类型的药物 Gabaar参与与衰老相关的功能的功能而没有影响 其他参与其他大脑功能的Gabaar，从而消除了大多数 药物副作用。