Epileptogenesis dynamics driven by peritumoral circuit rewiring in gangliogliomas

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Abstract Gangliogliomas (GGs) are emblematic low-grade epilepsy-associated tumors, yet the developmental mechanisms underlying their epileptogenicity remain unclear. Here, we investigated how tumor-network interactions evolve across postnatal maturation using an in-utero electroporated BRAF V600E -driven mouse model combining multiscale electrophysiology with histology, single-nucleus RNA sequencing, and complementary analyses in human GG tissue. We show that GGs induce early and evolutive modification of cortical organization and glioneuronal architecture. Despite glioneuronal preservation, seizure initiation shifted from distal cortical regions at postnatal stages to tumor-adjacent areas in adult networks. In both mouse and human, GG slices exhibited seizure activity localized to the peritumoral cortex. At the cellular level, neurons exhibited a developmental arrest of intrinsic electrophysiological maturation from postnatal to adult stages. Transcriptomic profiling identified stage-specific neuronal remodeling, with early alterations in inhibitory neurons and later changes affecting excitatory populations. Such developmental spatial seizure dynamics were associated with a pharmacological shift as NKCC1 inhibition with bumetanide selectively reduced seizure-like activity in neonatal but not mature tumor networks, indicating a restricted window of chloride-dependent epileptogenesis relevant to GABAergic maturation. Together, our results demonstrate that GG-associated epileptogenesis arises from developmentally regulated tumor-network interactions, highlighting distinct cellular and molecular mechanisms across maturation and revealing potential age-specific therapeutic targets.

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