ABSTRACT: Human brain development depends on the coordinated interaction of diverse cell types and extracellular matrix (ECM) components, essential for proper neurogenesis and cortical organization. Epidemiological and animal studies demonstrated that maternal immune activation (MIA) disrupts brain development, impairing neurogenesis and increasing the risk of neurodevelopmental disorders (NDDs), including autism spectrum disorder and schizophrenia. However, the cellular and molecular mechanisms by which MIA impacts human cortical development remain poorly understood. Here, we introduce a 3D ex vivo culture system, termed 'cerebroids,' derived from dorsolateral prefrontal cortex of human fetal brain tissue, which faithfully preserves key developmental processes, critical cellular diversity and structural integrity of the developing human cortex. Using this platform, we show that IL-17A, a cytokine strongly implicated in NDDs, induces premature cortical folding, increases cortical thickness, and accelerates neurogenesis and neuronal maturation. Transcriptomic and proteomic analyses reveal that IL-17A significantly dysregulates ECM-related pathways, including upregulation of proteoglycans such as Brevican and Versican. We further demonstrate that IL-17A directly activates NF-κB signaling in neural stem cells, leading to sustained inflammatory responses that contribute to these developmental abnormalities. Notably, treatment with the anti-inflammatory agent parthenolide, an inhibitor of NF-κB pathway, reverses IL-17A-induced cortical abnormalities, restoring normal cortical thickness, folding, and neurogenesis. These findings provide valuable insights into how IL-17A disrupts human cortical development during MIA, advancing our understanding of NDD-associated structural cortical alterations.
Muhammad Zaman Khan Assir 