Neurons stabilize their intrinsic excitability in response to prolonged and destabilizing changes in global activity by activity-dependent modification of their intrinsic membrane properties. Perturbation of this homeostatic intrinsic plasticity has been proposed to cause an imbalance between excitation and inhibition, leading to epilepsy. In addition to increasing the incidence of morbidity and mortality, epileptic seizures in the hippocampus critical for memory formation pose an enormous risk for a rapid progression of cognitive decline. Despite wide documentation, very little is known about the underlying mechanisms and the roles of homeostatic intrinsic plasticity in epileptogenesis. Here, we show that chronic inhibition of activity leads to a homeostatic increase in action potential firing rates in hippocampal neurons by decreasing calcium influx through N-Methyl-D-aspartate receptors. This homeostatic intrinsic plasticity is accompanied by a significant reduction in current and gene expression of K+ channels, one of which was Kv7/KCNQ channels. Conversely, a single stage-5 electroconvulsive seizure increases hippocampal expression of KCNQ channels in vivo. Considering that KCNQ channels give rise to voltage-dependent potassium current that suppress repetitive firing of action potentials, our data collectively indicate that repression of KCNQ channel genes serve as one important mechanism to mediate the stabilization of hippocampal neuronal excitability in the presence of chronic activity blockade. Furthermore, mutations in KCNQ channels are associated with inherited neonatal epilepsy. We also discover that some of these mutations disrupts the interaction of KCNQ channels with calmodulin, impairs their enrichment at the axonal surface by blocking their exit from the endoplasmic reticulum, and causes hippocampal neuronal excitability. Considering that calmodulin is a calcium sensor, these findings collectively suggest that dynamic transcriptional and trafficking regulation of KCNQ channels enriched in neuronal axons provide critical means to mediate homeostatic intrinsic plasticity and serve in the pathogenesis of epilepsy.