MODELING MATERNAL IMMUNE ACTIVATION REVEALS REGULATORY REMODELING IN HUMAN FOREBRAIN ORGANOIDS

Maternal immune activation (mIA) during pregnancy is associated with an increased risk of neurodevelopmental disorders, yet it remains unclear how brief inflammatory signals can exert long-lasting effects on human brain development. Here, we test the hypothesis that early immune exposure establishes durable molecular states in developing cortical cells that alter their responsiveness to later immune challenges. To address this, we used human forebrain organoids to study the effects of interleukin-17A (IL-17A), a cytokine strongly implicated in mIA models. Organoids were exposed to IL-17A during an early developmental window and followed over extended maturation, with or without a later immune challenge. Molecular responses were assessed using single-cell transcriptomic and chromatin accessibility profiling. Early IL-17A exposure triggered robust, cell-type-specific molecular changes, most prominently in radial glial and early neuronal lineages. Importantly, these changes persisted long after cytokine withdrawal, indicating durable alterations in developmental gene regulation. When organoids that had experienced an early immune challenge were exposed to IL-17A again at later stages, they responded differently than organoids encountering IL-17A for the first time. This altered responsiveness suggest that early immune exposure reshapes future molecular responses rather than simply causing transient stress. Across conditions, affected gene regulatory programs converged on pathways involved in neurogenesis, inflammatory signaling, and neuronal maturation. Together, our findings support a model in which early inflammatory signals establish a lasting molecular context that shapes how the developing human cortex responds to later immune challenges, providing a human developmental framework for understanding how immune timing and recurrence contribute to neurodevelopmental vulnerability.