IL-17A Alters Human Cortical Development in a 3D Ex Vivo Model of Maternal Immune Activation

Abstract

Human brain development depends on the coordinated interaction of diverse cell types and extracellular matrix (ECM) components, which are essential for proper neurogenesis and cortical organization. Epidemiological and animal studies have demonstrated that maternal immune activation (MIA) disrupts brain development, leading to impaired neurogenesis and increased risk of neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) 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, along with 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 significant dysregulation of ECM-related pathways, including the upregulation of proteoglycans such as brevican and versican. Notably, treatment with the anti-inflammatory agent parthenolide, an inhibitor of NF-{kappa}B and HDAC1 pathways, 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.