Junctional instability in neuroepithelium and network hyperexcitability in a focal cortical dysplasia human model

Abstract

Abstract Focal cortical dysplasia (FCD) is a highly epileptogenic cortical malformation with few treatment options. Here we generated human cortical organoids from patients with FCD type II. Using this human model, we mimicked some FCD hallmarks, such as impaired cell proliferation, the presence of dysmorphic neurons and balloon cells, and neuronal network hyperexcitability. Furthermore, we observed alterations in the adherens junctions zonula occludens-1 and partitioning defective 3, reduced polarization of the actin cytoskeleton, and fewer synaptic puncta. FCD cortical organoids showed downregulation of the small GTPase RHO A, a finding that was confirmed in brain tissue resected from these patients. Functionally, both spontaneous and optogenetically-evoked electrical activity revealed hyperexcitability and enhanced network connectivity in FCD organoids. Taken together, our findings suggest a ventricular zone instability in tissue cohesion of neuroepithelial cells, leading to a maturational arrest of progenitors or newborn neurons, which may predispose to cellular and functional immaturity and compromise the formation of neural networks in FCD.