Functional Characterization Of Altered Neurodevelopmental Mechanisms In Autism Using Patient Specific Induced Pluripotent Stem Cells PDF Download

To date, numerous candidate genes have been associated with autism spectrum disorder (ASD) with many of these genes known to have important roles in synaptic function and the development of neural circuits. This suggests that certain neurobiological processes could be commonly altered in ASD. Therefore, although there is a great deal of clinical and genetic heterogeneity in ASDs, there may be convergent deficits in key molecular mechanisms which underlie the disease. Although this is encouraging, a lack of appropriate human-based models of complex neurodevelopmental disorders has greatly hindered investigations of convergent neurobiology in ASD. Patient-specific induced pluripotent stem cells (iPSCs) can be used to model brain region-specific neuronal development in genetic backgrounds known to result in certain pathological conditions. This ability to model neurodevelopment in vitro permits the characterization of disease mechanisms that manifest themselves during the early steps of brain development in ASD, facilitating the identification of common molecular mechanisms disrupted in this disorder. Importantly, the identification of common pathways in ASD that are disrupted in the early stages of disease development could serve as important candidate targets for therapeutic intervention. Patient-specific iPSC lines were derived from the whole blood of individuals affected with idiopathic ASD, and subsequently differentiated into cortical neurons for up to 135 days in culture. The findings of transcriptome and gene network analysis indicate that iPSC-derived neurons from our cohort of ASD individuals have altered expression of genes associated with synaptic function, Wnt signaling, neuronal differentiation, and various processes involving the extracellular matrix (i.e. axon guidance and cell migration). Furthermore, our data show that genes previously implicated in ASD and intellectual disability are significantly overrepresented in gene coexpression networks related to synaptic function that are transcriptionally co-regulated by Wnt. Finally, we demonstrate that neurons derived from our sample cohort of idiopathic ASD individuals have excessive neurite outgrowth at an early stage of cortical neurogenesis. In sum, our data indicate that convergent molecular disturbances in ASD impact synaptic development and function, metabolism, and cellular molecular interactions involving the extracellular matrix. Furthermore, our results from transcriptome and gene-network analysis both indicate considerable transcriptional dysregulation during earlier stages of neuronal development.