CELLULAR MECHANISMS OF INHIBITORY TRANSMISSION

抑制传播的细胞机制

• 批准号: 3861149
• 负责人: STEVEN ROTHMAN
• 金额: --
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3861149
• 关键词: GABA receptor; acidity /alkalinity; anticonvulsants; brain disorder chemotherapy; brain electrical activity; butyrolactone; calcium flux; cellular pathology; electrophysiology; epilepsy; evoked potentials; gamma aminobutyrate; hippocampus; laboratory rat; neural transmission; neurons; neurotransmitters; newborn animals; synapses; tissue /cell culture; voltage /patch clamp

The overall objective of this proposal is to study the neurobiology and neuropharmacology of inhibitory synaptic transmission in the mammalian central nervous system. Our studies will be directed toward defining some of the cellular mechanisms of GABAnergic neurotransmission. Major goals are to: 1. define the role(s) of neuroactive butyrolactones and chemically related compounds in modulating the electrophysiological effects of GABA; 2. identify possible modulatory effects of GABA on intracellular pH and free calcium concentration; and 3. elucidate some characteristics of presynaptic GABA release. Our experiments will be done with hippocampal neurons cultured from neonatal rats and will utilize whole cell recording techniques in either current-clamp or voltage-clamp mode. The results of these experiments should improve our understanding of the mechanisms used by the brain to limit the spread of electrical activity and may help in the development of better drugs for the treatment of epilepsy and other neurological disorders. Specifically, we plan to: 1a.Examine many of the compounds described in Projects 1 and 2 to ascertain whether they are receptor agonists (diminish GABA-mediated chloride currents), inverse agonists (enhance GABA-mediated chloride currents), antagonists (block agonists and inverse agonists without having a direct effect on GABA currents), or inactive (at the GABA receptor). 1b.Examine interactions between butyrolactones and other compounds known to act at the GABA(A) receptor (GABA(A) agonists, benzodiazepines, and barbiturates). 1c.Determine whether butyrolactones up- or down-regulate GABA(A) receptors in cultured hippocampal neurons. 2.Determine whether GABA can directly alter the pH or intracellular calcium of cultured hippocampal neurons. 3a.Physiologically estimate the concentration of GABA actually released at inhibitory synapses. 3b.Determine whether GABA release in the central nervous system is always dependent on calcium entry.

该提案的总体目标是研究神经生物学和 哺乳动物抑制性突触传递的神经药理学 中枢神经系统。我们的研究将旨在定义一些 GABA能神经传递的细胞机制。主要目标是 目的： 1. 定义具有神经活性的丁内酯和化学物质的作用 调节 GABA 电生理效应的相关化合物； 2. 确定 GABA 对细胞内 pH 值的可能调节作用 游离钙浓度； 3. 阐明一些特征 突触前 GABA 释放。我们的实验将用海马体进行 从新生大鼠中培养的神经元将利用全细胞记录 电流钳或电压钳模式下的技术。结果 这些实验应该可以提高我们对所使用机制的理解 由大脑限制电活动的传播，可能有助于 开发更好的药物来治疗癫痫和其他疾病 神经系统疾病。 具体来说，我们计划： 1a.检查项目 1 和 2 中描述的许多化合物以确定 它们是否是受体激动剂（减少 GABA 介导的氯 电流）、反向激动剂（增强 GABA 介导的氯电流）、 拮抗剂（阻断激动剂和反向激动剂，没有直接作用） 对 GABA 电流的影响），或不活跃（对 GABA 受体）。 1b.检查丁内酯和其他已知的化合物之间的相互作用 作用于 GABA(A) 受体（GABA(A) 激动剂、苯二氮卓类药物和 巴比妥类药物）。 1c.确定丁内酯是否上调或下调GABA(A)受体 在培养的海马神经元中。 2.确定GABA是否可以直接改变pH或细胞内钙 培养的海马神经元。 3a.生理学估计实际释放的 GABA 浓度 抑制性突触。 3b.确定中枢神经系统中GABA的释放是否始终 依赖于钙的进入。