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Junctional instability in neuroepithelium and network 1 hyperexcitability in a focal cortical dysplasia human model

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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, 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. Our findings suggest a ventricular zone instability, leading to maturational arrest of progenitors, which may compromise the formation of neural networks in FCD.