ENDOGENOUS GABAERGIC ACTIVITY IN THE MAMMALIAN BRAIN

描述(改编自申请人的摘要)：本提案的目标 是对基本和独特特征的持续表征 哺乳动物中枢神经系统的GABA受体功能和突触。鉴于 已知的GABA能抑制改变在几个神经和 精神障碍，以及与GABA相关的作用机制 许多临床使用的药物，如抗焦虑药物，麻醉药和 抗惊厥药物，拟议的研究将大大有助于 对抑制及其被药物或神经元改变的认识 活动。每个具体目标都解决了与 GABA能抑制的调节。这些目标是：(1)建立 中间神经元抑制控制的特异性，导致 对GABA神经元网络同步激活的认识 负责大脑高频振荡的计时；(2) 洞察调控细胞和分子机制 GABA的释放和调控其同步性；以及(3)揭示分子 影响突触GABA-A受体功能的变化 慢性BZ治疗后的耐受性和停药情况。首先，录音来自 单独的解剖鉴定的海马区中间神经元将提供 首个综合生理和解剖相结合的指纹图谱 这些细胞。这一发现有望解释准确的突触 控制神经元间网络，被称为关键时钟 皮质中的高频(伽马)振荡，进而被认为是 更高级的皮质功能是其基础。其次，这项研究将探讨前和后 突触后因子，包括GABA-B受体和突触小泡 蛋白质，参与GABA释放的同步性。这些因素是 对于将中间神经元的高频放电转化为 精确定时的GABA释放，严格控制其他细胞的活动 中间神经元和主细胞。提案的第三部分将 解决苯扎酮耐受性和戒断问题，这是一个相当临床的话题 关联性。我们将检验突触GABA受体的假说 功能是由磷酸化控制的，而这种变化 过程可能是BZ耐受和停药的基础。由此产生的见解 关于GABA短期和长期运作的关键问题 突触将有助于更好地把握与之相关的许多临床问题 包括认知功能在内的抑制功能的改变 流程。对GABA能调节的深入认识 抑制可能开启旨在毁灭性的新治疗方法 精神和神经退行性疾病包括焦虑，压力， 中风和癫痫。

DESCRIPTION (adapted from applicant's abstract): The goal of this proposal is the continued characterization of fundamental and distinctive features of GABA receptor function and synapses of the mammalian CNS. In light of the known alterations of GABAergic inhibition in several neurological and psychiatric disorders, and of the GABA-related mechanism of action of numerous clinically used drugs such as anxiolytics, anesthetics and anticonvulsants, the proposed studies will considerably contribute to the understanding of inhibition and its alteration by drugs or neuronal activity. Each specific aim addresses a critical issue related to the regulation of GABAergic inhibition. These aims are: (1) to establish the specifics of the inhibitory control of interneurons, leading to understanding of the synchronous activation of GABA neuronal networks responsible for the timing of high frequency oscillations in the brain; (2) to gain insight into the cellular and molecular mechanisms which regulate GABA release and govern its synchrony; and (3) to uncover molecular alterations affecting the function of synaptic GABA-A receptors during tolerance and withdrawal after chronic BZ treatment. First, recordings from individual anatomically identified hippocampal interneurons will provide the first comprehensive combined physiological and anatomical fingerprinting of these cells. The findings are expected to explain the precise synaptic control of the interneuronal network, known as the critical clock for the high-frequency (gamma) oscillations in the cortex, in turn thought to underlie higher cortical function. Second, the study will probe pre- and postsynaptic factors, including GABA-B receptors and synaptic vesicle proteins, involved in the synchrony of GABA release. These factors are crucial for translating the high frequency discharges of interneurons into a precisely timed GABA release which tightly controls the activity of other interneurons and principal cells. The third part of the proposal will address BZ tolerance and withdrawal, a topic of considerable clinical relevance. We will examine the hypothesis that synaptic GABA receptor function is controlled by phosphorylation, and that alterations in this process may underlie BZ tolerance and withdrawal. The resulting insights into critical aspects of the short and long-term functioning of GABA synapses will lead to a better grasp of many clinical problems associated with alterations in inhibitory function including those of cognitive processes. A thorough understanding of the regulation of GABAergic inhibition may open novel therapeutical approaches aimed at devastating psychiatric and neurodegenerative disorders including anxiety, stress, stroke, and epilepsy.