Analysis of synaptic function during neurogenesis and maturation in homogeneous populations of autism-affected GABAergic and glutamatergic neurons. B. A. DeRosa1, 2, 3, K. C. Belle1, 2, 3, J. M. Van Baaren1, 3, J. M. Lee1, 3, M. L. Cuccaro1, 2, 3, J. M. Vance1, 2, 3, M. A. Pericak-Vance1, 2, 3, D. M. Dykxhoorn1, 2, 3 1) John P. Hussman Institute for Human Genomics; 2) Dr. John T. Macdonald Foundation Department of Human Genetics; 3) University of Miami Miller Schoold of Medicine, Miami, Fl.

   Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by deficiencies in social interaction, verbal and non-verbal communication, and repetitive stereotyped behaviors. The lack of genetically relevant human disease models of ASD that can be used to study the pathogenic mechanisms that underlie this disorder has significantly impeded the development of novel therapeutic interventions. A number of recent studies have utilized post-mortem brain tissue obtained from individuals affected with ASD to study the biological mechanisms that give rise to the disorder. However, these samples represent a single time point, when the disease is fully manifested, limiting what can be learned about the disease process. With the use of patient-specific induced pluripotent stem cells (iPSCs), it is possible to generate large quantities of neurons with genetic backgrounds that are known to result in ASD. Furthermore, a number of methods are available that enable the differentiation of these iPSCs into the specific neuronal subtypes that are most likely to be affected by ASD-specific genetic backgrounds. The in vitro differentiation of the specific neuronal subtypes closely mimics in vivo neurogenesis and synaptic maturation allowing us to characterize the impact of autism on neurodevelopmental processes. For this purpose, we have generated a panel of iPSC lines from peripheral blood samples obtained from 7 ASD patients. These ASD iPSCs are able to be differentiated into functionally active GABAergic and glutamatergic cortical-like neurons. Furthermore, we have developed a set of lentiviral-based human promoter-driven fluorescent reporters of GABAergic neurons, glutamatergic neurons, and development-stage in neurogenesis. These cell type-specific fluorescent reporters allow the isolation of these specific neuronal cell types from heterogeneous cell populations in culture via fluorescence-activated cell sorting. A comparative analysis of the homogeneous populations of ASD-affected and unaffected control iPSC-derived neurons show abnormalities in expression patterns of genes involved in synaptic function and pathways that include genes previously associated with ASD. The use of ASD-specific iPSC-derived neurons provides a novel approach to understand the complex cellular and molecular processes that govern these disorders opening up new opportunities for the development of novel therapeutic approaches.

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