Modeling Epilepsies with Human Brain Organoids: Recent Advances and Ongoing Challenges

Epilepsy is a common and heterogeneous group of neurologic disorders characterized by recurrent unprovoked seizures. With a diverse array of genetic and acquired etiologies, the mechanisms linking insults to epileptogenesis and network hyperexcitability remain poorly understood. Although animal models have provided critical insights into seizure generation and disease mechanisms, differences in human cortical development and limitations in recapitulating spontaneous seizure phenotypes observed in patients highlight the need to develop complementary human-based models. Human pluripotent stem cell-derived brain organoids, including patient-derived and CRISPR-engineered models, offer an increasingly powerful human-specific platform to investigate epilepsy-associated disruptions in neuronal production and differentiation, interneuron migration, and network activity. In this review, we discuss recent advances and ongoing challenges of human cortical organoid models of genetic and acquired epilepsies. Together with established animal models, organoid-based approaches hold promise for advancing mechanistic understanding of epilepsy and enabling the development of more precise therapeutic strategies.