CELL TYPE–SPECIFIC EFFECTS OF INCREASED PERSISTENT SODIUM CURRENT ON NEURONAL FIRING

SCN1A variants underlie a wide phenotypic spectrum. Loss-of-function (LOF) variants are mainly associated with Dravet syndrome and GEFS+, whereas gain-of-function (GOF) variants were initially linked to hemiplegic migraine and more recently to diverse epileptic phenotypes, ranging from severe neonatal epileptic encephalopathy to milder, later-onset epilepsies. Patients with GOF variants often benefit from sodium channel blockers, which typically worsen LOF-associated phenotypes, underscoring the need for functional characterization.
We previously identified mutation-specific sodium channel dysfunctions using heterologous expression systems. Here, we investigated the impact of increased persistent sodium current (INaP), a common GOF feature, on neuronal firing using dynamic clamp experiments in acute mouse brain slices. This technique integrates real-time computational modeling with electrophysiological recordings to inject defined, voltage-dependent sodium conductances into intact neurons, enabling selective manipulation of INaP while preserving native cellular context.
Increasing INaP in pyramidal neurons and somatostatin-positive GABAergic interneurons reduced depolarization block thresholds and slowed action potentials, consistent with reduced excitability. In contrast, fast-spiking parvalbumin-positive GABAergic interneurons exhibited increased firing rates and delayed depolarization block.
Identical GOF sodium channel alterations can produce divergent functional effects across neuronal subtypes. These findings highlight the complexity of SCN1A-related pathophysiology and emphasize the importance of cell type–specific functional studies to guide precision therapies and clinical trial design.