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 GABRA?2 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 cartridges and GABA related proteins with immunochemistry, Ch cells with Golgi staining, and analyze synapse 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 autistic group (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 is necessary to move the field of autism research in a new direction. This project will provide a thorough understanding of the GABAergic system in the human cerebral cortex in autism, and will have a great impact on translational research directed towards providing novel treatment for individuals with autism. !
We propose to define the role of Chandellier cells in autism by unraveling their morphological and connectional properties. This project will provide a thorough understanding of the GABAergic system in the human cerebral cortex in autism, and will have a great impact on translational research directed towards providing novel treatment for individuals with autism.
|Martínez-Cerdeño, Verónica; García-Moreno, Fernando; Tosches, Maria Antonietta et al. (2018) Update on forebrain evolution: From neurogenesis to thermogenesis. Semin Cell Dev Biol 76:15-22|
|Liu, Fang; Horton-Sparks, Kayla; Hull, Vanessa et al. (2018) The valproic acid rat model of autism presents with gut bacterial dysbiosis similar to that in human autism. Mol Autism 9:61|
|Martínez Cerdeño, Verónica; Hong, Tiffany; Amina, Sarwat et al. (2018) Microglial cell activation and senescence are characteristic of the pathology FXTAS. Mov Disord :|
|Martínez-Cerdeño, Verónica; Lechpammer, Mirna; Hagerman, Paul J et al. (2017) Two FMR1 premutation cases without nuclear inclusions. Mov Disord 32:1328-1329|
|Martínez-Cerdeño, Verónica (2017) Dendrite and spine modifications in autism and related neurodevelopmental disorders in patients and animal models. Dev Neurobiol 77:393-404|
|Martínez-Cerdeño, Verónica; Lechpammer, Mirna; Noctor, Stephen et al. (2017) FMR1 premutation with Prader-Willi phenotype and fragile X-associated tremor/ataxia syndrome. Clin Case Rep 5:625-629|
|Ariza, Jeanelle; Rogers, Hailee; Hartvigsen, Anna et al. (2017) Iron accumulation and dysregulation in the putamen in fragile X-associated tremor/ataxia syndrome. Mov Disord 32:585-591|
|Lechpammer, Mirna; Martínez Cerde?o, Verónica; Hunsaker, Michael Ryan et al. (2017) Concomitant occurrence of FXTAS and clinically defined sporadic inclusion body myositis: report of two cases. Croat Med J 58:310-315|
|Hashemi, Ezzat; Ariza, Jeanelle; Rogers, Haille et al. (2017) The Number of Parvalbumin-Expressing Interneurons Is Decreased in the Prefrontal Cortex in Autism. Cereb Cortex 27:1931-1943|
|Rogers, Hailee; Ariza, Jeanelle; Monterrubio, Angela et al. (2016) Cerebellar Mild Iron Accumulation in a Subset of FMR1 Premutation Carriers with FXTAS. Cerebellum 15:641-4|
Showing the most recent 10 out of 27 publications