Preferential inactivation of Scn1a in parvalbumin interneurons increases seizure susceptibility.

Voltage-gated sodium channels (VGSCs) are essential for the generation and propagation of action potentials in electrically excitable cells. Dominant mutations in SCN1A, which encodes the Nav1.1 VGSC α-subunit, underlie several forms of epilepsy, including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+).

Protective effect of the ketogenic diet in Scn1a mutant mice.

Purpose: We evaluated the ability of the ketogenic diet (KD) to improve thresholds to flurothyl-induced seizures in two mouse lines with Scn1a mutations: one that models Dravet syndrome (DS) and another that models genetic (generalized) epilepsy with febrile seizures plus (GEFS+).

Methods: At postnatal day 21, mouse models of DS and GEFS+ were fasted for 12-14 h and then placed on either a 6:1 (fats to proteins and carbohydrates) KD or a standard diet (SD) for 2 weeks. At the end of the 2-week period, we measured thresholds to seizures induced by the chemiconvulsant flurothyl.

Altered function of the SCN1A voltage-gated sodium channel leads to gamma-aminobutyric acid-ergic (GABAergic) interneuron abnormalities.

Voltage-gated sodium channels are required for the initiation and propagation of action potentials. Mutations in the neuronal voltage-gated sodium channel SCN1A are associated with a growing number of disorders including generalized epilepsy with febrile seizures plus (GEFS+),(7) severe myoclonic epilepsy of infancy, and familial hemiplegic migraine. To gain insight into the effect of SCN1A mutations on neuronal excitability, we introduced the human GEFS+ mutation SCN1A-R1648H into the orthologous mouse gene.

Genetic influences on ketogenic diet efficacy.

An average of 15-20% of patients on the ketogenic diet (KD) experience a >50% reduction in seizure frequency; however, 10-40% discontinue the diet due to either a lack of response or adverse side effects. This variability in patient response raises the possibility that genetic factors may influence the efficacy of the KD. As a first step towards identifying these factors, we evaluated the ability of the KD to alter seizure thresholds in four commonly used inbred mouse strains: C57BL/6J, FVB/NJ, A/J, and DBA/2J.