KCNQ2 Loss-of-Function variants disrupt neuronal maturation via early hyperexcitability followed by maladaptive network remodeling

Dirkx, N.; Kaji, M.; De Vriendt, E.; Carleo, G.; Miceli, F.; Asselbergh, B.; Verstraelen, P.; Carotenuto, L.; Dang, L. T.; Sommers, V.; Vlaemynck, E.; Lagae, L.; Ceulemans, B.; De Jonghe, P.; De Vos, W. H.; Taglialatela, M.; Weckhuysen, S.; Zonnekein, N.

doi:10.1101/2025.07.22.664856

bioRxiv · 10.1101/2025.07.22.664856

KCNQ2 Loss-of-Function variants disrupt neuronal maturation via early hyperexcitability followed by maladaptive network remodeling

Dirkx, N.·Kaji, M.·De Vriendt, E.·Carleo, G.·Miceli, F.·Asselbergh, B.·Verstraelen, P.·Carotenuto, L.·Dang, L. T.·Sommers, V.·Vlaemynck, E.·Lagae, L.·Ceulemans, B.·De Jonghe, P.·De Vos, W. H.·Taglialatela, M.·Weckhuysen, S.·Zonnekein, N.

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Abstract

Loss-of-function (LOF) variants in the potassium channel subunit KCNQ2 cause a spectrum of neonatal epilepsies from self-limiting familial neonatal epilepsy (SeLFNE) to severe developmental and epileptic encephalopathy (DEE). To dissect the developmental consequences of KCNQ2 LOF, we conducted a longitudinal and multimodal comparative analysis in a human neuronal model generated from patients with KCNQ2-DEE and KCNQ2-SeLFNE. KCNQ2-LOF induced a biphasic network dysfunction, with early Kv7-driven hyperexcitability rescued by acute Retigabine (RTG) treatment, followed by maladaptive remodeling in the opposite direction. Transcriptomic analysis mirrored this biphasic dynamic trajectory, revealing an initial upregulation followed by a subsequent downregulation of synaptic genes. Structural analysis showed a steeper decline in presynaptic density alongside a distal shift in the axon initial segment (AIS) throughout maturation, and impaired AIS plasticity at later stages. Overall, KCNQ2-LOF disrupts human neuronal maturation through dynamic, biphasic changes in function, gene expression and structure, offering insights into disease mechanisms and therapeutic options.

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Dirkx, N., Kaji, M., De Vriendt, E., Carleo, G., Miceli, F., Asselbergh, B., Verstraelen, P., Carotenuto, L., Dang, L. T., Sommers, V., Vlaemynck, E., Lagae, L., Ceulemans, B., De Jonghe, P., De Vos, W. H., Taglialatela, M., Weckhuysen, S., Zonnekein, N.. 2025-07-24. KCNQ2 Loss-of-Function variants disrupt neuronal maturation via early hyperexcitability followed by maladaptive network remodeling. https://doi.org/10.1101/2025.07.22.664856

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