Atypical neurogenesis and excitatory-inhibitory progenitor generation in induced pluripotent stem cell (iPSC) from autistic individuals

Autism is a set of neurodevelopmental conditions with a complex genetic basis. Previous induced pluripotent stem cell (iPSC) studies with autistic individuals having macroencephaly have revealed atypical neuronal proliferation and GABA/glutamate imbalance, the latter also being observed in magnetic resonance spectroscopy (MRS) studies. Functional genomics of autism post mortem brain tissue has identified convergent gene expression networks. However, it is not clear whether the established autism phenotypes are observed in the wider autism spectrum. It also not known whether autism-associated in vivo gene expression patterns are recapitulated during in vitro neural differentiation. To examine this we have generated induced pluripotent stem cells (iPSCs) from a cohort of autistic individuals with heterogeneous backgrounds, which were differentiated into early and late neural precursors, and early neural cells using an in vitro model of cortical neurogenesis. We observed atypical neural differentiation of autism iPSCs compared with controls, and dynamic imbalance in GABA/glutamate cell populations over time. RNA-sequencing identified altered gene co-expression networks associated with neural maturation and GABA/glutamate imbalance, and these pathways correlated with pathways in post-mortem brains. Autism neural cells also recapitulated autism post mortem immune pathways, and found CD44, an autism-associated gene, to be predicted as a highly connected gene. In conclusion, our study demonstrates significant differences in neural differentiation between autism and control iPSCs including GABA/glutamate precursor imbalance, and significant preservation of atypical autism-associated gene networks observed in other model systems.