Chandellier interneurons and the excitation/inhibition balance in the human prefrontal cortex in autismLittle is known about the pathology of the cerebral cortex in autism. The goal of our previously funded R01grant was to unravel the pathology of the cerebral cortex in patients with autism. Specifically, we proposed todiscover which cell type(s), if any, are altered in the cerebral cortex of human autistic cases. We quantified thenumber of pyramidal neurons, specific subtypes of interneurons, and glial cells, within each layer of the humantemporal and prefrontal cortex in autism. We determined that the number of pyramidal neurons and glial cellsin 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, wediscovered that there is a decrease in the number of one specific interneuronal subtype in the prefrontal cortexof autistic cases, the parvalbumin (PV)+ Chandellier cell (Hashemi et al., 2016). Chandellier (Ch) cells are themain interneuron in the cortex possessing axons that synapse directly on the initial segment of the pyramidalaxon, creating a prominent structure called “cartridge”. Consequently, the Ch cell is the main interneuronalsubtype that regulates the final output of excitatory projection neurons. Therefore, the loss of a small number ofCh cells may critically impair function of pyramidal cells and of the cerebral cortex as a whole. Indeed, changesin Ch cells cartridges/boutons and/or function have previously been reported in neurological diseases, such asschizophrenia and epilepsy. Based on our discovery, we propose to define the role of Ch cells in autism byunraveling their morphological and connectional properties.We hypothesize that the decreased number of PV+ Ch cells we discovered in the autistic cortex translates intoa 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, andultimately impaired function of cortical projection neurons. We also hypothesize that there is a decreasedamount of GABA and GABA related proteins per cartridge, and of GABRAα2 receptors in the pyramidal axonalinitial segment. This reduction of inhibitory synapse structure would cause hyperexcitation of cortical synapticcircuits in autism. Additionally, we hypothesize that in autism there is a negative correlation between theseverity 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 analteration 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 willlabel cartridges and GABA related proteins with immunochemistry, Ch cells with Golgi staining, and analyzesynapse structure with 3D electronic microscopy. We will analyze data using Stereoinvestigator, Neurolucida,Image J, FIB/SEM EM, and high-throughput 3D reconstruction. We will correlate data obtained for the autisticgroup (Aim 1-3) with specific symptoms and other patient characteristics.Providing a comprehensive quantification of the elements of the GABA system in the autism cerebral cortex isnecessary to move the field of autism research in a new direction. This project will provide a thoroughunderstanding of the GABAergic system in the human cerebral cortex in autism, and will have a great impacton translational research directed towards providing novel treatment for individuals with autism.!
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
