Using Human Induced Neural Precursor Cells to Define Early Neurodevelopmental Defects in Syndromic and Idiopathic Autism

Purpose of Review Autism spectrum disorder (ASD) is characterized as a developmental brain disorder with a complex and undefined etiology. While animal studies have been beneficial to identify mechanisms behind monogenic causes of ASD, 80% of the disorder is idiopathic or genetically undefined. This review explores current models of autism that use induced pluripotent stem cell (iPSCs) technology as a means to address underlying mechanisms, as well as specific cellular processes and methods which should receive greater attention considering ASD pathophysiology. Recent Findings ASD risk factor genes are overwhelmingly expressed during fetal development, during a time when neural precursor cells (NPCs) undergo early cellular processes such as proliferation, migration, and differentiation. Further, transcriptomic analyses of human iPSCs, iPSC-derived neural precursors, and postmitotic neurons most closely resemble cortical cells of the first and second trimesters of fetal development. Thus, studying NPCs derived from ASD individuals may be beneficial. However, studies have focused primarily on iPSC-derived postmitotic neurons with little attention paid to NPCs. Yet, two studies using NPCs derived from idiopathic patients found on average that proliferation was greater compared to unaffected controls. Additional investigations have also partially examined proliferative phenotypes within monogenic, copy number variant, and idiopathic forms of autism. Of interest, some of these studies require lengthy, labor intensive culturing methods which can limit high throughput capacity. Recent approaches have adapted and developed high throughput assays for use in monolayer culture to quickly screen precursors for abnormalities in cellular proliferation, migration, and neurite outgrowth and assay for potential therapeutic interventions. Summary Genetic and neuropathological studies suggest that multiple aspects of ASD converge on fetal developmental processes such as proliferation, migration, and differentiation within the cerebral cortex. Thus, iPSC-derived NPCs are an excellent model to study genetic and cellular aspects of ASD. While NPC studies are currently limited, they have already begun to identify phenotypes for monogenic, copy number variant, and idiopathic forms of ASD. Our understanding of ASD pathophysiology could be furthered by additional NPC-based studies examining these early neurodevelopmental processes. New methods showcased in this review have begun to identify differences in proliferation, migration, and neurite outgrowth for multiple subgroups of autism, as well as identify common neurobiological phenotypes among autism subgroups. Future NPC studies employing these methods can screen for defects in relevant signaling pathways, as well as begin to define person-specific therapeutic drugs in a high throughput manner.