INVESTIGATING SEIZURE ONSET AND FIRING RATE ALTERATIONS IN THE DEVELOPING HIPPOCAMPUS OF AN SCN2A (P.A263V) MOUSE MODEL

The voltage-gated sodium channel Nav1.2, encoded by SCN2A, is essential for action potential generation during early brain development. In both humans and mice, Nav1.2 predominates at the axon initial segment (AIS) of pyramidal neurons during neonatal stages and is progressively replaced by Nav1.6 as the brain matures. Pathogenic SCN2A variants are strongly associated with neurodevelopmental disorders, including epilepsy and autism spectrum disorders.
This study focuses on the gain-of-function p.A263V SCN2A variant, which causes severe neonatal and infantile epilepsy but can show age-dependent seizure remission. A leading hypothesis suggests that remission reflects the developmental switch from Nav1.2 to Nav1.6 at the AIS. However, neurological impairments often persist after seizures subside, indicating lasting circuit dysfunction. We generated a mouse model carrying the Scn2a p.A263V mutation and observed spontaneous hippocampal seizures from postnatal day 2–3. Heterozygous, but not homozygous, mice showed complete seizure remission after postnatal day 20, coinciding with the Nav1.2-to-Nav1.6 switch. Using in vivo Neuropixels recordings and activity-
dependent c-Fos staining, we assessed hippocampal activity across development. Our results identify abnormal CA3 activity as a key driver of early seizures. Despite pyramidal neuron hyperexcitability, overall hippocampal activity outside seizures is reduced early in development, consistent with compensatory inhibitory mechanisms. After remission, pyramidal neuron activity normalizes, while interneuron activity remains altered, suggesting persistent circuit-level changes in SCN2A-related disorders.