Roles of GABAAR Subunits in Hippocampal Inhibition and Oscillations

描述(申请人提供)：在整个神经系统中，GABAA受体介导的抑制控制神经元网络活动。在海马体内，不同的中间神经元利用不同的GABAA受体亚型控制和协调在学习和记忆中发挥关键作用的电路中的活动。在阿尔茨海默病和癫痫等疾病中，这些回路也容易受到病理变化的影响，它们利用的受体是许多临床药物的靶标；了解它们的组织和功能直接关系到人类的健康。我们建议检验一种假设，即含有GABAA受体a5和03亚单位的受体在海马CA1区的树突层大量表达，有助于慢突触抑制，它们有助于控制对重复刺激的反应，以及它们参与网络振荡的产生或表达。为了验证这些假说，我们确定了三个特定的目标：1)测试CT5和33亚基对体外培养的海马锥体神经元抑制的贡献；2)测试a5和33亚基对体外培养的海马神经元综合细胞特性和网络功能的贡献；3)测试a5和33亚基对海马网振荡的贡献。为了实现这些目标，我们将遵循遗传学和药理学相结合的方法，使用具有内在亚基选择性或通过亚基特定突变而具有选择性的基因靶向小鼠和药物。这项研究的长期目标是将单个亚单位和突触的属性与活动模式和网络反应联系起来，这些活动模式和网络反应是学习和记忆等认知功能的基础。

DESCRIPTION (provided by applicant): Throughout the nervous system, GABAA receptor-mediated inhibition controls neuronal network activity. Within the hippocampus, diverse interneurons that utilize a variety of GABAA receptor subtypes control and coordinate activity in circuits that play crucial roles in learning and memory. These circuits are also susceptible to pathological changes in conditions such as Alzheimer's disease and epilepsy, and the receptors that they utilize are the targets of many clinically used drugs; understanding their organization and function are directly relevant to human health. We propose to test the hypothesis that receptors containing the GABAA receptor a5 and 03 subunits, which are heavily expressed in the dendritic layers of the hippocampal CA1 region, contribute to slow synaptic inhibition, that they are instrumental in controlling responses to repetitive stimulation, and that they participate in the generation or expression of network oscillations. To test these hypotheses we have identified three specific aims: 1) test the contributions of ct5 and (33 subunits to inhibition in hippocampal pyramidal neurons in vitro; 2) test the contributions of a5 and (33 subunits to integrative cellular properties and network function in the hippocampus in vitro; and 3) test the contributions of a5 and (33 subunits to hippocampal network oscillations. To accomplish these aims we will follow a combined genetic and pharmacologic approach, using gene-targeted mice and drugs that have intrinsic subunit selectivity or are rendered selective by subunit-specific mutations. The long term-goal of this research is to relate the properties of individual subunits and synapses to activity patterns and network responses that underlie cognitive functions such as learning and memory.