Plasticity of GABA-Mediated Inhibition

描述(由申请人提供) 在计划项目(修订)的续签申请中，同一机构加州大学洛杉矶分校的两名额外教员与正在进行的三名调查人员共同努力。接下来是理查德·奥尔森博士、卡罗琳·豪泽博士和伊斯特万·莫迪博士。迈克尔·范斯洛博士和汤姆·奥蒂斯博士是新成员。该项目名为“GABA介导的抑制的可塑性”。这项研究汇集了生物化学、行为学、电生理学、神经解剖学以及分子和细胞生物学方面的专业知识。计划成员将联合起来解决基础神经生物学中的重要问题，这些问题对任何一个人来说都是困难的。几个重要的问题，其中可塑性的GABA能抑制发挥关键作用，将被解决。每组研究将涉及几个研究者之间的相互作用，如：1)神经类固醇对GABAR介导的抑制的影响；2)乙醇对GABAR介导的特定类型的抑制的影响；3)GABAR调节剂停用后的神经元可塑性；4)GABAR的翻译后调制和运输；5)稳态神经元的可塑性；6)GABAR介导的学习抑制；7)含有GABAR的突触外α4/6-β-增量亚单位介导的紧张性抑制在神经类固醇、乙醇和麻醉剂的作用中，以及在各种可塑性中。该计划中的组件还将检查海马体抑制，重点是含有Alpha4 Delta的GABAR，以及GABAR Delta亚单位基因敲除小鼠和其他基因工程动物的海马体和小脑的抑制方面。其中一个项目将考虑在不同时间框架内的可塑性诱导活动期间和之后的兴奋和抑制的平衡。它在大脑中的主要作用使GABA成为伴随经历的正常可塑性机制的主要参与者。通过让啮齿动物，或者在某些情况下，细胞和切片，受到一些不寻常的经验，被认为涉及GABA，我们将研究由此产生的长期修饰的分子和细胞机制。更好地了解涉及GABA的可塑性现象与正常大脑功能和疾病过程高度相关，并可能建议治疗。最相关的是癫痫、压力、焦虑和惊恐障碍、睡眠障碍和药物依赖(酒精和苯二氮卓类药物)。拟议的实验程序的复杂性需要一个研究团队的专业知识，每个团队都拥有广泛的分析工具。总而言之，这些工具产生了一个强大的实验方法组合，这些方法属于团队，而不是属于任何一个团队成员。该计划项目的所有成员都致力于共同努力，成功地弥合中枢神经系统中行为和分子事件之间的差距。

DESCRIPTION (provided by applicant) In this renewal application of the program project (revised), two additional faculty at the same institution, UCLA, have combined efforts with the ongoing three investigators. Continuing are Drs. Richard Olsen, Carolyn Houser, and Istvan Mody. New are Drs. Michael Fanselow and Tom Otis. The Program Project is named "Plasticity of GABA-mediated Inhibition". The research brings together expertise in biochemistry, behavior, electrophysiology, neuroanatomy, and molecular and cell biology. Program members will combine to approach important questions in basic neurobiology which would be difficult for any one individual. Several important topics in which plasticity of GABAergic inhibition plays a crucial role will be addressed. Each set of studies will involve interactions among several investigators as indicated: 1) Effects of neurosteroids on GABARmediated inhibition; 2) Effects of ethanol on specific types of GABAR-mediated inhibition; 3) Neuronal plasticity following withdrawal of GABAR modulators; 4) Post-translational modulation and trafficking of GABAR; 5) Homeostatic neuronal plasticity; 6) GABAR-mediated inhibition in learning; 7) Involvement of extrasynaptic alpha4/6-beta-delta subunit-containing GABAR-mediated tonic inhibition in the action of neurosteroids, ethanol, and anesthetics, and in various sorts of plasticity. Components in the program also will examine hippocampal inhibition, with a focus on alpha4delta-containing GABAR, and aspects of inhibition in hippocampus and cerebellum in the GABAR delta subunit knockout mice and other genetically engineered animals. One project will consider the balance of excitation and inhibition during and after plasticity-inducing activities with various time frames. Its predominant role in the brain makes GABA a major player in the normal plasticity mechanisms that accompany experiences. By subjecting rodents, or in some cases, cells and slices, to somewhat extraordinary experiences that are considered to involve GABA, we will investigate the molecular and cellular mechanisms of the long-term modifications resulting. Better understanding of plasticity phenomena involving GABA has high relevance to normal brain function and to disease processes and may suggest treatments. Most relevant are epilepsy, stress, anxiety, and panic disorders, sleep disorders, and drug dependence (alcohol and benzodiazepines). The complexity of the proposed experimental procedures requires the expertise of a team of investigators, each with a wide spectrum of analytical tools. Together, these tools yield a powerful combination of experimental approaches vested in the group rather than in any single team member. All members of the Program Project are committed to working together to successfully bridge the gap between behavior and molecular events in the CNS.