DISRUPTED NETWORK MATURATION AND EXCITABILITY IN <EM>SCN2A</EM> CHANNELOPATHIES: A WINDOW FOR EARLY INTERVENTION

Nav1.2, encoded by SCN2A, is essential for action potential generation in immature neurons. Accordingly, SCN2A mutations cause a spectrum of neurodevelopmental disorders: loss-of-function (LoF) variants are typically associated with autism spectrum disorder, while gain-of-function (GoF) variants cause early-onset epilepsies, ranging from self-limited familial neonatal-infantile epilepsy (SeLFNIE) to severe developmental and epileptic encephalopathies (DEEs).
Informed by scRNA-seq data showing peak transcriptomic changes at P7, we asked whether neonatal hippocampal network activity reveals signatures of altered excitability and disrupted maturation. We performed in vivo local field potential (LFP) recordings from the hippocampus at P6-P7 in a GoF model (patient-derived p.A263V) and two Scn2a LoF models (heterozygous knockout and patient-derived p.L1314P). The amplitude of early sharp waves was increased in p.A263V GoF mice (Reva et al., 2025; bioRxiv doi:10.1101/2025.06.29.661458) and decreased in heterozygous knockout, while unexpectedly unchanged in LoF p.L1314P mice. These excitability changes align with in vitro and transcriptomic findings, though network activity patterns typical of this developmental stage were preserved.
Given early seizure onset, limited efficacy of postnatal treatment, and the Nav1.2 developmental switch, we also tested whether a single perinatal intervention could prevent epilepsy emergence. We administered Scn2a-targeting antisense oligonucleotides (ASOs) via in utero intracerebroventricular injection at E14.5. Strikingly, ASO-treated homozygous mice were seizure-free at P7 (0/6 vs 6/8 untreated). Ongoing work will determine whether protection persists into adulthood.
Together, these findings reveal genotype-specific alterations in early network excitability and demonstrate that perinatal intervention can prevent seizures in Scn2a GoF channelopathies.