Testing the Excitability of Inhibitory Neurons

描述（由申请人提供）：神经系统疾病，如癫痫和脆性X综合征（FXS），其特征是兴奋性和抑制性神经传递不平衡。FXS患者表现出过度兴奋的表型，表现为严重的认知缺陷、复发性癫痫发作的发生率增加、社交焦虑和对感官刺激的过度敏感。我们假设初级体感觉皮层的抑制性神经传递缺陷是FXS过度兴奋表型的基础，包括其与癫痫的合并症。在这个项目中，我们使用多学科方法结合电生理和解剖分析与小鼠遗传救援研究脆性X在皮层区域相关的认知和感觉功能障碍的表型。我们的主要目标是确定FXS中突触和网络功能障碍的机制。我们将通过两种互补理论的观点来研究抑制性神经元功能障碍，这两种理论被假设导致在FXS中观察到的过度兴奋表型。我们还将测试FXS突变小鼠抑制回路的兴奋性改变是否可以从基因上恢复。

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.