Endogenous Gabaergic Activity

项目总结/摘要 哺乳动物大脑的GABA能系统由释放GABA的神经元和结合GABA的受体组成。 GABA释放GABA的细胞非常多样化和高度专业化。一些GABA能细胞 控制局部网络（interneurons，IN）中的活动，而其他神经元则构成一个定义明确的 结构（例如，纹状体中棘神经元，MSN）。GABA的受体也是多样和特异的。 配体门控GABA受体（GABAARs）是Cys环受体家族的成员，几乎存在于 大脑中的每一个神经元，并根据它们的突触或突触外 本地化位于突触外（突触内或突触外）的GABAAR被GABA激活 存在于细胞外空间的分子。这些GABAAR介导一种"始终开启"的抑制， 也称为紧张性抑制。在上一个资助期内完成的研究， 与紧张性抑制的性质、药理学和起源相关的基本机制。直接 继续上一个资助期间进行的研究，本项目将侧重于 紧张性GABA传导在细胞/网络兴奋性和神经保护中的新的和未经测试的作用。 该提案将使用最先进的电生理学，显微镜， 分子药理学、光学和转基因小鼠技术。该假说假定， 活性GABAAR介导的传导对于保护大脑中高度脆弱的神经元至关重要 对抗过度兴奋和神经毒性其目的是集中在两个容易受损的大脑区域， 这种电导是存在的，但可以在各种条件下改变。拟议的研究将 阐明紧张性GABA传导抑制过度同步的机制， 高兴奋性海马CA3区以及它如何保护新纹状体神经元免受神经毒性。 考虑到CA3区域的极度兴奋性及其与癫痫的相关性，以及高的 新纹状体对功能障碍和变性的易感性，这些实验将解决中枢神经系统的问题。 与癫痫、亨廷顿病（HD）、抽动秽语综合征的病理学和治疗相关的问题 (TS)以及边缘系统和纹状体的其他疾病。这些研究预计将产生新的 用于治疗与神经元相关的疾病的对紧张性抑制特异的药理学干预 同步性，包括癫痫和认知障碍，以及用于治疗或预防神经变性 纹状体和其他易受损伤的大脑结构的状况。

Project Summary/Abstract The GABAergic system of the mammalian brain consists of neurons that release GABA and receptors that bind GABA. The GABA-releasing cells are extraordinarily diverse and highly specialized. Some GABAergic cells control the activity in a local network (interneurons, INs), while others constitute the output of a well-defined structure (e.g., striatal medium spiny neurons, MSNs). The receptors for GABA are also diverse and specific. Ligand-gated GABA receptors (GABAARs), members of the Cys-loop receptor family, are present on virtually every neuron in the brain and perform different functions depending on their synaptic or extrasynaptic localization. The GABAARs located outside the synapses (peri- or extrasynaptically) are activated by GABA molecules present in the extracellular space. These GABAARs mediate a type of inhibition that is "always on", also termed tonic inhibition. The studies completed during the past funding period have addressed fundamental mechanisms related to the nature, pharmacology and origin of tonic inhibition. As a direct continuation of the research carried out during the previous funding period, the present project will focus on novel and untested roles of the tonic GABA conductance in cellular/network excitability and neuroprotection. The proposal will address a specific hypothesis using state-of-the-art electrophysiological, microscopical, molecular pharmacological, optical, and transgenic mouse technologies. The hypothesis posits that a tonically active GABAAR-mediated conductance is essential for protecting highly vulnerable neurons in the brain against hyperexcitability and neurotoxicity. The aim is to focus on two damage-prone brain regions where this conductance is present, but can be altered under various conditions. The proposed studies will elucidate the mechanisms whereby the tonic GABA conductance dampens excessive synchrony in the hyperexcitable hippocampal CA3 region and how it protects neostriatal neurons against neurotoxicity. Considering the extremely excitable nature of the CA3 region and its relevance to epilepsy, and the high susceptibility of the neostriatum to dysfunction and degeneration, these experiments will address central issues related to the pathologies and treatments of epilepsies, Huntington's disease (HD), Tourette¿s syndrome (TS) and other disorders of the limbic system and striatum. The studies are expected to generate novel pharmacological interventions specific for tonic inhibition for the treatment of disorders related to neuronal synchrony including epilepsy and cognitive disorders, and for treating or preventing neurodegenerative conditions of the striatum and other damage-prone brain structures.