Cortical circuit dysfunction in fragile x syndrome

 描述（由申请人提供）：负责神经发育障碍中认知功能障碍的皮层抑制性微电路的身份在很大程度上仍然未知，尽管它们能够以行为相关频率控制和调节大脑中的网络同步。脆性X综合征（FXS）是一种神经发育障碍，其特征是智力残疾和自闭症的主要单基因原因。虽然许多研究关注兴奋性回路功能障碍，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，例如复发性癫痫发作的发生率增加，社交焦虑和对感觉刺激的超敏反应。我们最近发表的工作说明缺陷激活生长抑素阳性低阈值尖峰（Sst-LTS）抑制性中间神经元在小鼠模型FXS。我们现在将使用多学科方法，将电生理学，行为和光遗传学技术与遗传拯救小鼠相结合，研究中间神经元缺陷群体如何影响FXS中的细胞，电路和行为特性。这些实验的共同目标是确定皮层回路抑制功能的波动如何影响药理学和网络可塑性。具体 目的1将确定Sst-LTS中间神经元的错误激活改变细胞功能和Sst-LTS中间神经元与其靶点之间的通信的多种机制。具体目标2将研究大规模的网络特性，需要功能齐全的interneurona微电路。我们的研究结果将为研究皮层中间神经元之间的关系及其在疾病可塑性中的作用提供新的重要领域的基础。此外，这些研究将有助于阐明FXS表型中观察到的认知和行为缺陷的矫正恢复的潜在治疗策略。

 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.