Cortical circuit dysfunction in fragile x syndrome

 描述(申请人提供)：皮质抑制微电路负责神经发育障碍的认知功能障碍，尽管它们有能力控制和调节大脑中与行为相关的频率的网络同步，但其身份在很大程度上仍不清楚。脆性X综合征(FXS)是一种神经发育障碍，是导致智力残疾和自闭症的主要单基因原因。虽然许多研究都集中在兴奋性回路功能障碍上，但FXS表型的许多方面都指向与抑制性神经传递缺陷相关的问题，如反复癫痫发作的发生率增加，社交焦虑和对感觉刺激的高敏感性。我们最近发表的工作说明了生长抑素阳性低阈值尖峰(SST-LTS)抑制中间神经元在FXS小鼠模型中的缺陷激活。我们现在将使用一种融合了电生理学、行为学和光遗传学技术与遗传拯救小鼠的多学科方法来研究有缺陷的中间神经元群体如何影响FXS的细胞、电路和行为特性。这些实验的共同目标是确定皮质环路抑制功能的波动如何影响药理学和网络可塑性。特定的 目的1确定SST-LTS中间神经元的激活错误改变细胞功能和SST-LTS中间神经元与其靶点之间的通讯的多种机制。具体目标2将研究需要完全功能的神经元间微电路的大规模网络特性。我们的发现将为研究皮质中间神经元之间的关系及其在疾病可塑性中所扮演的角色提供新的和重要的领域的基础。此外，这些研究将有助于阐明纠正FXS表型中观察到的认知和行为缺陷的潜在治疗策略。

 DESCRIPTION (provided by applicant): The identity of cortical inhibitory microcircuits responsible for cognitive dysfunction in neurodevelopmental disorders remains largely unknown, despite their capacity to control and regulate network synchrony in the brain at behaviorally relevant frequencies. Fragile X Syndrome (FXS) is a neurodevelopmental disorder characterized as the leading monogenetic cause of intellectual disability and autism. While many studies focus on excitatory circuit dysfunction, many aspects of the FXS phenotype point to problems associated with inhibitory neurotransmission defects such as increased incidence of recurring seizures, social anxiety and hypersensitivity to sensory stimuli. Our recently published work illustrates defective activation of somatostatin-positive low-threshold spiking (Sst-LTS) inhibitory interneurons in a mouse model of FXS. We will now use a multidisciplinary approach merging electrophysiology, behavior and optogenetic technology with genetic rescue mice to study how a defective population of interneurons affects cellular, circuit and behavioral properties in FXS. The collective goal of these experiments is to determine how fluctuations in inhibitory function of cortical circuits affect both pharmacologic and network plasticity. Specific Aim 1 will identify the multiple mechanisms by which faulty activation of Sst-LTS interneurons alters cellular function and communication between Sst-LTS interneurons and their targets. Specific Aim 2 will study large scale network properties that require fully functional interneurona microcircuits. Our findings will provide the basis for new and important areas of investigation into the relationship between cortical interneurons and the roles they play in the plasticity of disease. Moreover, these studies will aid in the elucidation of potential therapeutic strategies fo the corrective restoration of cognitive and behavioral deficits observed in the FXS phenotype.