Testing the Excitability of Inhibitory Neurons

描述(由申请人提供)：癫痫和脆性X综合征(FXS)等神经疾病的特征是兴奋性和抑制性神经传递的失衡。FXS患者表现出高度兴奋的表型，表现为严重的认知障碍、反复发作的发生率增加、社交焦虑和对感觉刺激的高敏感性。我们假设初级躯体感觉皮层抑制性神经传递的缺陷是FXS过度兴奋表型的基础，包括其与癫痫的共病。在这个项目中，我们使用多学科的方法结合电生理学和解剖学分析以及小鼠的遗传拯救来研究与认知和感觉功能障碍相关的皮质区域中的脆性X表型。我们的主要目标是确定FXS中突触和网络功能障碍的机制。我们将通过两个互补理论的观点来检查抑制性神经元功能障碍，这两个理论假设导致在FXS中观察到的超兴奋表型。我们还将测试抑制回路中改变的兴奋性是否可以在FXS突变小鼠中得到遗传挽救。

DESCRIPTION (provided by applicant): Neurological disorders such as epilepsy and Fragile X Syndrome (FXS) are characterized with imbalances in excitatory and inhibitory neurotransmission. Patients with FXS exhibit a hyperexcitable phenotype evidenced by severe cognitive deficits, increased incidence of recurring seizures, social anxiety and hypersensitivity to sensory stimuli. We hypothesize that defects in inhibitory neurotransmission in primary somatosensory cortex underlie aspects of the hyperexcitable phenotype of FXS, including its comorbidity with epilepsy. In this project, we use a multidisciplinary approach combining electrophysiological and anatomical analyses with mouse genetic rescues to study the Fragile X phenotype in a cortical area relevant for both cognitive and sensory dysfunction. Our primary goals are to determine the mechanism of synaptic and network dysfunction in FXS. We will examine inhibitory neuron dysfunction through the view of two complementary theories that are hypothesized to lead to the hyperexcitable phenotype observed in FXS. We will additionally test whether altered excitability in inhibitory circuits can be rescued genetically in FXS mutant mice.