Cortical and subcortical chandelier cell pathophysiology and symptomatology in autism

摘要 我们资助的第一笔R01拨款的目标是解开人类前额叶改变的细胞类型(S) 自闭症谱系障碍(ASD)患者的大脑皮质(PFC)我们发现吊灯(CH)细胞的数量减少了 在ASD患者死后人体组织的PFC中。在我们的第一个更新的R01中，我们建议定义角色 ASD患者PFC中CH细胞的表达。我们发现PFC内CH细胞的GABA系统成分发生了改变 患有自闭症。在这里，在我们的第二次R01续订申请中，我们建议通过确定CH来跟进我们的研究 PFC、其他皮质区域和皮质下区域的细胞病理生理学与ASD症状的相关性 已知与自闭症有关。CH细胞是调节兴奋性投射的最终输出的中间神经元。 大脑皮层、海马体和杏仁核中的神经元。因此，单个CH信元的损失可能会严重 损害投射神经元的正常功能和整体解剖结构。这项提案将探讨 大脑皮层和皮质下多个区CH细胞数量紊乱的假说 与ASD大脑中报告的GABA能系统的功能改变有关。我们还假设 齿状回内CH细胞数量的减少转化为ASD神经发生的降低。我们 也将检验CH细胞的病理生理改变之间存在相关性的假设 以及患者症状的严重程度。我们将通过量化CH细胞的数量来检验这些假设 ASD中新皮质(目标1a，b)、海马结构(目标2a，c)和杏仁核(目标3a，b)的特定区域， 并将这些数字与患者的行为相关联。我们还将评估祖细胞的数量和 ASD齿状回未成熟神经元(目标2b)。PFC外CH细胞的数量和功能 尚未在ASD中进行评估。我们的建议解决了这一知识差距。这项工程将极大地 扩大我们对GABA能CH系统在ASD中作用的理解，这将对ASD产生重大影响 转化性研究旨在为ASD患者提供更好的治疗范例。

Abstract The goal of our first funded R01 grant was to unravel the cell type(s), if any, altered in the human prefrontal cortex (PFC) in autism spectrum disorder (ASD). We discovered a decreased number of Chandelier (Ch) cells in the PFC of postmortem human tissue in ASD patients. In our first renewed R01 we proposed to define the role of Ch cells in the PFC in ASD. We found an alteration of components of the GABA system in Ch cells in the PFC in autism. Here, in our second R01 renewal application, we propose to follow up our studies by determining Ch cell pathophysiology association to ASD symptomatology in PFC, other cortical areas, and in subcortical areas known to be involved in ASD. Ch cells are the interneurons that regulates the final output of excitatory projection neurons in the neocortex, hippocampus, and amygdala. Therefore, the loss of a single Ch cell may critically impair proper function of projection neurons and the anatomical structure as a whole. This proposal will explore the hypothesis that disturbances in Ch cell number in several areas of the cerebral cortex and subcortical areas contribute to the altered function of the GABAergic system reported in the ASD brain. We also hypothesize that a decreased number of Ch cells in dentate gyrus translates into a decreased rate of neurogenesis in ASD. We will also test the hypothesis that there is a correlation between the pathophysiological alterations of Ch cells and the severity of patient’s symptoms. We will test these hypotheses by quantifying the number of Ch cells in specific areas of the neocortex (aim 1a,b), hippocampal formation (aim 2a,c), and amygdala (aim 3a,b) in ASD, and correlating these numbers with patient behavior. We will also assess the number of progenitor cells and immature neurons in the dentate gyrus in ASD (aim 2b). The number and function of Ch cells outside the PFC has not yet been evaluated in ASD. Our proposal addresses this gap in knowledge. This project will greatly expand our understanding of the GABAergic Ch system function in ASD, which will have a great impact on translational research directed towards providing better treatment paradigms for individuals with ASD.