Dravet Syndrome is a developmental and epileptic encephalopathy, with intractable seizures and other comorbidities; due to loss of function variants in SCN1A, the disease mostly manifests because of the impairment of the functionality of inhibitory interneurons. Trying to address the unmet clinical needs of patients carrying missense variants, we used a transgenic mouse model carrying the recurrent variant p.(Ala1783Val) in Scn1a. This mouse closely recapitulates the clinical phenotype, allowing to more deeply explore the epileptogenesis and find new precision medicine approaches.We carried out single-nuclei RNA-seq (snRNA-seq) in the cortex and performed single-cell patch-clamp of L5 pyramidal neurons, before and after seizure onset. We tried to pharmacologically restore the normal levels of excitability, carrying out paired recordings before and after the application of M-current-targeting drugs.With the snRNA-seq, we found that several potassium channel genes were dysregulated in excitatory neurons of the cortex, before (P16) and after seizure onset (P20). We show that these alterations give rise to a hyperexcitability phenotype in pyramidal neurons, with a decrease of rheobase and an increase in the input resistance and firing frequency. We used retigabine and its derivative c60 to try reactivating the transcriptomically dysregulated KV7 channel family and revert this phenotype and found that 1 μM c60 but not 1 μM retigabine can completely restore the cortical hyperexcitability to wild-type levels.We conclude that the transcriptomic dysregulation of potassium channels in excitatory cortical neurons contributes to neuronal hyperexcitability, which can be restored to wild-type levels upon pharmacological activation of KV7 channels.