Early postnatal CA3 hyperexcitability drives hippocampal development and epileptogenesis in SCN2A developmental and epileptic encephalopathy

Reva, Y.; Ulrich, K.; Xin, X.; Liu, Y.; Barboni, M.; Kirianov, D.; Mojtahedi, N.; Schoeb, S.; Oelssner, H.; Savitska, D.; Samehni, M.; Xompero, F.; Schulze, E.; Beck, H.; Morellini, F.; Engeland, B.; Stockebrand, M.; Marguet, S. L.; Khodosevich, K.; Garaschuk, O.; Kelly, T.; Fazeli, W.; Lerche, H.; Isbrandt, D.

doi:10.1101/2025.06.29.661458

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bioRxiv · 10.1101/2025.06.29.661458

Early postnatal CA3 hyperexcitability drives hippocampal development and epileptogenesis in SCN2A developmental and epileptic encephalopathy

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Abstract

Developmental and epileptic encephalopathies caused by pathogenic variants in SCN2A (SCN2A-DEE), encoding the voltage-gated sodium channel Nav1.2, present with early-life seizures, developmental delay, and increased mortality. Using a novel Scn2a p.A263V gain-of-function (GOF) mouse model, we demonstrate gene-dose and background-dependent phenotypes ranging from self-limited neonatal seizures to chronic epilepsy with high mortality. In vivo electrophysiology revealed hippocampal seizures as early as postnatal day 2.5, with CA3-driven gamma oscillations preceding seizure onset. CA3 and CA1 pyramidal neurons exhibited transient hyperexcitability during early postnatal development, resolving by P24-30. Single-cell RNA sequencing uncovered gene dose-dependent accelerated maturation of hippocampal networks, peaking at P7, alongside widespread transcriptional changes in excitatory and inhibitory neurons. In adulthood, persistent hippocampal network alterations emerged, marked by reduced mid-gamma oscillations and theta-gamma coupling. Our findings establish hippocampal CA3 hyperexcitability as an early driver of epileptogenesis in SCN2A-DEE and highlight it as a potential therapeutic target to mitigate disease progression.

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Reva, Y., Ulrich, K., Xin, X., Liu, Y., Barboni, M., Kirianov, D., Mojtahedi, N., Schoeb, S., Oelssner, H., Savitska, D., Samehni, M., Xompero, F., Schulze, E., Beck, H., Morellini, F., Engeland, B., Stockebrand, M., Marguet, S. L., Khodosevich, K., Garaschuk, O., Kelly, T., Fazeli, W., Lerche, H., Isbrandt, D.. 2025-06-29. Early postnatal CA3 hyperexcitability drives hippocampal development and epileptogenesis in SCN2A developmental and epileptic encephalopathy. https://doi.org/10.1101/2025.06.29.661458

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