Cortical and subcortical chandelier cell pathophysiology and symptomatology in autism

摘要 我们的第一个资助R01基金的目标是解开细胞类型（S），如果有的话，在人类前额叶皮层中改变 自闭症谱系障碍（ASD）中的皮质（PFC）。我们发现吊灯（Ch）细胞数量减少， 在ASD患者死后人体组织的前额叶皮层中在我们第一次更新的R01中，我们建议定义 ASD患者PFC中Ch细胞的数量。我们发现PFC中Ch细胞的GABA系统成分发生了改变 孤独症。在我们的第二次R01更新申请中，我们建议通过确定Ch 细胞病理生理学与PFC、其他皮质区和皮质下区ASD病理学的相关性 已知与自闭症有关Ch细胞是调节兴奋性投射最终输出的中间神经元 新皮层海马体和杏仁核的神经元。因此，单个Ch单元的损失可能严重地 损害投射神经元和整个解剖结构的正常功能。该提案将探讨 大脑皮质和皮质下区域多个区域的Ch细胞数量失调的假设 有助于ASD大脑中报告的GABA能系统功能的改变。我们还假设， 齿状回中Ch细胞数量的减少转化为ASD中神经发生速率的降低。我们 还将检验Ch细胞的病理生理学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细胞中Ch细胞的数量来测试这些假设。 ASD中的新皮质（aim 1a，B）、海马结构（aim 2a，c）和杏仁核（aim 3a，B）的特定区域， 并将这些数字与病人的行为联系起来。我们还将评估祖细胞的数量， ASD中齿状回中的未成熟神经元（目的2b）。PFC外Ch细胞的数量和功能 尚未在ASD中进行评估。我们的建议填补了这一知识空白。该项目将大大 扩展我们对ASD中GABA能Ch系统功能的理解，这将对 转化研究旨在为ASD患者提供更好的治疗模式。

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.