Human Cellular Models of Autism and Related Conditions

Human cellular models are enabling the in vitro study of the complex molecular and cellular mechanisms underlying autism spectrum disorder (ASD). Human embryonic stem cell (hESC) and induced pluripotent stem cell (hiPSC)- derived models have progressed from investigating single genes to multiplexed approaches that have allowed the study of several ASD risk genes in parallel, which have expanded our understanding of how coding and noncoding genetic variants shape cellular and molecular phenotypes in ASD. Additionally, these models have identified several convergent pathogenic mechanisms in ASD, including dysregulated neurogenesis, altered cell type specification (such as defects in glutamatergic neurons and expansion of GABAergic neurons), and disrupted synaptic activity. Common molecular principles are also emerging, including dysregulation of chromatin, WNT signaling, and mTOR signaling. hiPSC models of ASD have also been used to evaluate the effect of several FDA-approved therapeutic compounds on early human neural development, such as mTOR inhibitors, some of which are currently in clinical trials for ASD-related conditions. Although human cellular models have limitations, their unique strength is the ability to reveal early developmental pathophysiology and the potential to correlate in vitro phenotypes with the clinical features of patient donors. Here, we examine how human cellular models have advanced basic and translational research in ASD and identify key cellular and molecular convergent phenotypes that have emerged.