CELLULAR MECHANISMS OF INHIBITORY TRANSMISSION

抑制传播的细胞机制

• 批准号: 3782679
• 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/3782679
• 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.

这项建议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。我们的研究将致力于定义一些 GABA能神经传递的细胞机制。主要目标是 1.确定神经活性丁内酯的作用(S)和化学 调节GABA电生理效应的相关化合物； 2.确定GABA对细胞内pH和 游离钙浓度；以及3.阐明一些特性 突触前GABA释放。我们的实验将在海马区进行 从新生大鼠培养的神经元将利用全细胞记录 技术在电流钳位或电压钳位模式。结果是 这些实验应该会提高我们对所用机制的理解。 通过大脑来限制电活动的传播，并可能有助于 开发更好的治疗癫痫和其他疾病的药物 神经紊乱。 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，无直接作用 对GABA电流的影响)，或不活跃(在GABA受体上)。 1b.丁内酯与已知的其他化合物之间的相互作用 作用于GABA(A)受体(GABA(A)激动剂、苯二氮卓类和 巴比妥酸盐)。 1c.测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是否能直接改变pH或细胞内钙离子 培养的海马神经元。 3a.生理上估计实际释放的GABA浓度在 抑制性突触。 3b.确定中枢神经系统中GABA的释放是否总是 依赖于钙离子进入。