Chandellier interneurons and the excitation/inhibition balance in the human prefrontal cortex in autism Little is known about the pathology of the cerebral cortex in autism. The goal of our previously funded R01 grant was to unravel the pathology of the cerebral cortex in patients with autism. Specifically, we proposed to discover which cell type(s), if any, are altered in the cerebral cortex of human autistic cases. We quantified the number of pyramidal neurons, specific subtypes of interneurons, and glial cells, within each layer of the human temporal and prefrontal cortex in autism. We determined that the number of pyramidal neurons and glial cells in the temporal cerebral cortex of autistic cases did not differ from that in typically developing control cases, and published our results in several research articles (Camacho et al., 2014; Kim et al., 2015). However, we discovered that there is a decrease in the number of one specific interneuronal subtype in the prefrontal cortex of autistic cases, the parvalbumin (PV)+ Chandellier cell (Hashemi et al., 2016). Chandellier (Ch) cells are the main interneuron in the cortex possessing axons that synapse directly on the initial segment of the pyramidal axon, creating a prominent structure called “cartridge”. Consequently, the Ch cell is the main interneuronal subtype that regulates the final output of excitatory projection neurons. Therefore, the loss of a small number of Ch cells may critically impair function of pyramidal cells and of the cerebral cortex as a whole. Indeed, changes in Ch cells cartridges/boutons and/or function have previously been reported in neurological diseases, such as schizophrenia and epilepsy. Based on our discovery, we propose to define the role of Ch cells in autism by unraveling their morphological and connectional properties. We hypothesize that the decreased number of PV+ Ch cells we discovered in the autistic cortex translates into a decrease in the number of Ch cell cartridges and a decrease in the number of synaptic buttons per cartridge, with the consequent loss of Ch symmetric synapses on the pyramidal neuron axonal initial segment, and ultimately impaired function of cortical projection neurons. We also hypothesize that there is a decreased amount of GABA and GABA related proteins per cartridge, and of GABRAα2 receptors in the pyramidal axonal initial segment. This reduction of inhibitory synapse structure would cause hyperexcitation of cortical synaptic circuits in autism. Additionally, we hypothesize that in autism there is a negative correlation between the severity of the patient' symptoms and the number of Ch cells. We will determine if there is an alteration in the number and length of Ch cell cartridges (Aim1), if there is an alteration in the GABAergic system in Ch cartridges (Aim 2), and if there is an alteration in the number of axo- axonic synapses (Aim 3) in the prefrontal cortex (BA9, BA45, BA46) of the autism postmortem brain. We will label cartrid...