Transgenic mouse models of sodium and potassium channelopathies in epilepsy: insights into disease mechanisms and therapeutics.

Brain-expressed voltage-gated sodium (Nav) and potassium (Kv) channels are essential for maintaining the balance of neuronal excitability, each having opposing effects on membrane potential and neuronal firing. Genetic alterations in these channels can disrupt this balance, leading to epilepsy and/or developmental impairments through gain-of-function (GoF) or loss-of-function (LoF) mechanisms. This review catalogs 48 transgenic mouse models involving sodium channels (SCN1A, SCN2A, SCN3A, SCN8A) and potassium channels (KCNQ2, KCNQ3, KCNT1, KCNA1, KCNB1, KCND2), detailing the effects of genetic alterations in terms of channel function, affected cell types, and phenotypic manifestations. Mechanistic insights from these models reveal that initial channel dysfunction triggers cascading pathological processes including glutamate excitotoxicity, oxidative stress, gliosis, neuroinflammation, and blood-brain barrier disruption. Therapeutic approaches include antisense oligonucleotides to enhance functional allele expression or reduce pathogenic channel expression, viral-mediated gene therapy, gene editing, and small molecule modulators that target persistent sodium currents or that stabilize channel inactivation. The timing of intervention appears to be critical, with early treatment showing greater efficacy in preventing pathological cascades. Strain-specific background effects and compensatory ion channel expression affect phenotypic severity and treatment response, complicating translation of model results. Importantly, transgenic models offer opportunities to better understand mechanisms underlying comorbidities commonly suffered by patients, including behavioral disorders, motor impairments, and sleep disturbances. The integration of these findings suggests that effective treatment strategies may require combinations of channel-directed therapies and interventions targeting downstream pathological processes, particularly for established disease. This comprehensive examination of channelopathy models provides a framework for developing transformative therapeutics for genetic epilepsies.