CEREBRAL ORGANOIDS UNCOVER HUMAN-SPECIFIC MECHANISMS OF NETWORK HYPERACTIVITY IN TUBEROUS SCLEROSIS COMPLEX

Neurological disorders often originate from progressive brain network dysfunction that starts years before symptoms appear. How these changes emerge in the developing human brain remains elusive due to a lack of tractable model systems. Here, we show a cerebral organoid model of Tuberous Sclerosis Complex (TSC) that recapitulates hallmarks of epileptogenesis in vitro. We compare extracellular recordings from TSC organoids with intraoperative electrocorticography from TSC patients, revealing striking functional similarities, including pathological high-frequency oscillations – an electrical biomarker for epileptogenic tissue. In TSC, a human-specific interneuron subtype derived from the caudal ganglionic eminence drives pathological network phenotype through perturbed synaptic transmission, as confirmed by extracellular recordings during pharmacological treatments, miniature inhibitory postsynaptic current recordings, and electron microscopy of inhibitory synapses. This leads to an altered excitation/inhibition (E/I) ratio and increased spontaneous firing. Moreover, inhibiting the overproliferation of its progenitors via long-term epidermal growth factor receptor inhibition prevented the onset of this pathological phenotype at both functional and morphological levels. Our work shows that organoids enable mechanistic analysis of emerging neural network phenotypes, enabling anti-epileptogenic drug testing in a human brain development model.