Activity of voltage-gated Na channels (Nav) is modified by alternative splicing. However, whether altered splicing of human Navs contributes to epilepsy remains to be conclusively shown. We show here that altered splicing of theDrosophilaNav(paralytic,DmNav) contributes to seizure-like behavior in identified seizure mutants. We focus attention on a pair of mutually exclusive alternate exons (termedKandL), which form part of the voltage sensor (S4) in domain III of the expressed channel. The presence of exonLresults in a large, non-inactivating, persistentINap. Many forms of human epilepsy are associated with an increase in this current. In wild-type (WT)Drosophilalarvae, ∼70–80% ofDmNavtranscripts contain exonL, and the remainder contain exonK. Splicing ofDmNavto include exonLis increased to ∼100% in both theslamdanceandeasily-shockedseizure mutants. This change to splicing is prevented by reducing synaptic activity levels through exposure to the antiepileptic phenytoin or the inhibitory transmitter GABA. Conversely, enhancing synaptic activity in WT, by feeding of picrotoxin is sufficient to increaseINapand promote seizure through increased inclusion of exonLto 100%. We also show that the underlying activity-dependent mechanism requires the presence of Pasilla, an RNA-binding protein. Finally, we use computational modeling to show that increasingINapis sufficient to potentiate membrane excitability consistent with a seizure phenotype. Thus, increased synaptic excitation favors inclusion of exonL, which, in turn, further increases neuronal excitability. Thus, at least inDrosophila, this self-reinforcing cycle may promote the incidence of seizure.