Cortical and subcortical chandelier cell pathophysiology and symptomatology in autism

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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.