Endogenous GABAergic Activity

内源性 GABA 活性

基本信息

批准号：
7252539
负责人：
ISTVAN MODY
金额：
$ 38.77万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-05-01 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7252539
关键词：
Ablation Address Affect Affinity Agonist Anesthetics Anti-Anxiety Agents Anticonvulsants Anxiety Brain Cerebellum Chromosome Pairing Clinical Cognitive Cyclic AMP-Dependent Protein Kinases Development Disease Drug usage Electrons Endogenous Factors Epilepsy Exhibits Exposure to Extracellular Space Funding GABA Receptor Goals Individual Interneurons Investigation Kinetics Knowledge Lead Light Mediating Mental disorders Methods Microscopic Mus Mutant Strains Mice Neuraxis Neurologic Neurons Norepinephrine Pharmaceutical Preparations Pharmacology Phosphorylation Physiologic pulse Physiological Population Process Property Publishing Pulse taking Rattus Receptor Cell Regulation Research Resolution Role Role playing therapy Shapes Site Stress Stroke Synapses System Techniques Testing Transgenic Model abstracting desensitization gamma-Aminobutyric Acid grasp insight knockout animal nervous system disorder neuronal excitability novel postsynaptic receptor receptor function

项目摘要

DESCRIPTION: (Verbatim from the Applicant's Abstract) The goal of this proposal is to continue the characterization of fundamental and distinctive features of GABA receptor function and inhibitory mechanisms in the mammalian CNS. Alterations in GABAA receptor-mediated inhibition take place over the course of several neurological and psychiatric disorders, and numerous clinically used drugs including anxiolytics, anesthetics and anticonvulsants have GABAA receptor-dependent mechanisms of action. In light of this, the proposed studies will contribute to the understanding of inhibition and its alterations by neuronal activity, drugs or disease states. The proposal will characterize two distinct forms of GABAergic activity in central neurons: phasic inhibition mediated by activation of GABAA receptors at synapse, and tonic inhibition that is most likely generated by extrasynaptic receptors activated by ambient GABA present in the extracellular space. The central hypothesis to be tested is as follows: tonic and phasic GABAergic inhibition are separately generated and differently regulated in the central nervous system. Consequently, the two inhibitions perform distinct functions to control the excitability of individual neurons and of interconnected neuronal networks. Each specific aim addresses critical features of the two types of inhibition. These aims are: 1) to establish the differential pharmacology of the two types of inhibition; 2) to study their regulation by endogenous factors; 3) to resolve how the two inhibitions control the activity of interneurons; 4) to identify distinct subclasses of interneurons explicitly involved in producing one or the other type of inhibition; 5) to uncover the role played by the two types of inhibition in regulating the excitability of neuronal networks. To establish these goals, high resolution electrophysiological recordings will be obtained from neurons identified with IR-DIC and fluorescent methods. Light and electron microscopical investigations will address the specific anatomical properties and localization of the receptors and cells involved. Moreover, the study will use genetically altered mice that over- or under-express certain GABA receptors in specific neuronal populations. Other mutant mice have well-defined subclasses of interneuron expressing specific markers to facilitate their identification for electrophysiological recordings or for their specific photochemical ablation by exposure to UV light. The study is expected to yield novel and specific insights into the functioning of the GABAergic system in the brain. Understanding the role and the specific control of the two types of inhibition will lead to a better grasp of many clinical problems associated with alterations in inhibitory function including those underlying cognitive processes. A thorough knowledge of the regulation of GABAergic inhibition by endogenous factors and by specific drugs will open the possibility for novel therapies aimed at curing some devastating psychiatric and neurological disorders including anxiety, stress, stroke, and epilepsy.

描述：（逐字摘自申请人摘要）本提案的目标是继续描述基本特征和显着特征哺乳动物中枢神经系统中 GABA 受体的功能和抑制机制。 GABAA 受体介导的抑制作用发生变化多种神经和精神疾病，以及许多临床使用的抗焦虑药、麻醉药和抗惊厥药等药物含有 GABAA 受体依赖性作用机制。有鉴于此，拟议的研究将有助于理解抑制及其改变神经元活动、药物或疾病状态。该提案将有两个特点中枢神经元 GABA 活性的不同形式：阶段性抑制通过突触 GABAA 受体的激活和强直性抑制介导最有可能是由环境 GABA 激活的突触外受体产生存在于细胞外空间。要检验的中心假设是如下：分别产生强直性和阶段性 GABA 能抑制中枢神经系统受到不同的调节。因此，两人抑制执行不同的功能来控制兴奋性单个神经元和互连的神经元网络。每个具体目标解决了两种抑制的关键特征。这些目标是：1) 建立两种抑制作用的差异药理学； 2）研究内源因素对其的调节； 3）两者如何解决抑制控制中间神经元的活动； 4）识别不同的明确参与产生其中一种或另一种的中间神经元的子类抑制类型； 5）揭示两种类型所扮演的角色抑制调节神经网络的兴奋性。建立这些目标，将获得高分辨率的电生理记录来自用 IR-DIC 和荧光方法鉴定的神经元。光与电子显微镜研究将解决特定的解剖学特性以及相关受体和细胞的定位。此外，该研究将使用过度表达或表达不足的某些 GABA 受体的基因改造小鼠在特定的神经元群体中。其他突变小鼠具有明确的中间神经元的亚类表达特定标记以促进其电生理记录或其特定的识别通过暴露于紫外线进行光化学烧蚀。该研究预计将产生对 GABAergic 系统功能的新颖而具体的见解脑。了解两类的作用以及具体控制抑制将导致更好地掌握许多相关的临床问题抑制功能的改变，包括那些潜在的认知功能的改变流程。全面了解 GABA 能抑制的调节内源性因素和特定药物将为新型药物开辟可能性旨在治愈一些毁灭性的精神和神经疾病的疗法疾病包括焦虑、压力、中风和癫痫。