Modeling maternal immune activation in 3D ex vivo human fetal brain cerebroids reveals IL-17A-driven disruption of cortical development

Abstract

Maternal immune activation (MIA) disrupts brain development and increases the risk of neurodevelopmental disorders, yet the mechanisms by which MIA impacts human cortical development remain poorly understood. Here we introduce a three-dimensional ex vivo culture system, termed ‘cerebroids,’ derived from the dorsolateral prefrontal cortex of human fetal brain tissue, which preserves the key developmental processes, cellular diversity and structural integrity of the developing human cortex. Using this model, we show that IL-17A, a cytokine implicated in MIA and neurodevelopmental disorders, induces premature cortical folding, increases cortical thickness and accelerates neurogenesis and neuronal maturation. We reveal that IL-17A substantially dysregulates extracellular-matrix-related pathways, including upregulation of proteoglycans. In neural stem cells, IL-17A directly activates NF-κB signaling, leading to sustained inflammatory responses that contribute to these developmental abnormalities, which are reversed by treatment with the NF-κB pathway inhibitor parthenolide. These findings delineate how IL-17A perturbs human corticogenesis while elucidating the mechanisms underlying brain disruption during MIA. Using cerebroids, a 3D ex vivo model of the human fetal brain, the authors show that IL-17A, a mediator of maternal immune activation linked to neurodevelopmental disorders, disrupts early human cortical development through NF-κB signaling.