Pathological Priming and Developmental Heterochrony as Organizing Concepts in Human iPSC Models of Autism Spectrum Disorder.

Abstract

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition in which diverse genetic risk factors converge on molecular pathways governing early brain development. Human-induced pluripotent stem cell (iPSC) and brain organoid models now permit direct interrogation of these pathways in patient-derived neural tissue and, in a subset of studies, reveal alterations in neural progenitor proliferation, cortical neurogenesis, synaptic maturation, and network excitability. A landmark iPSC study in macrocephalic idiopathic ASD introduced the concept of pathological priming of neural progenitors, durable reconfiguration of chromatin and transcriptional states that biases downstream developmental programs, and associated developmental heterochrony in neuronal gene networks, thereby linking early progenitor biology to selectively shifted trajectories of neuronal maturation and to macrostructural and functional abnormalities. This conceptual review synthesizes evidence for pathological priming and developmental heterochrony from human iPSC-derived neurons and brain organoids, focusing on the ASD subgroups in which timing mechanisms are best supported: macrocephalic idiopathic ASD, 16p11.2 and related copy number variants, and large-effect developmental regulators such as SYNGAP1. We summarize recurrent and inconsistent cellular and circuit phenotypes, evaluate multi-omic data implicating progenitor regulatory states in shaping developmental timing, and situate timing-focused mechanisms alongside synaptopathy, excitatory-inhibitory imbalance, critical-period, and neuroimmune models. We propose that disturbances in neurodevelopmental timing characterize specific ASD subgroups, particularly those with early brain overgrowth or large-effect developmental regulators, rather than ASD as a whole, and offer a useful organizing principle for integrating divergent findings and generating testable, timing-informed hypotheses for future experimental and translational work.