Dravet in the dish: mechanisms of hyperexcitability.

Commentary Dravet syndrome, formerly known as Severe Myoclonic Epilepsy of Infancy (SMEI), is a devastating neurodevelopmental disorder of intractable epilepsy that begins in early infancy. Tragically, development of affected children is typically on track during the first year of life, whereas progressive developmental decline and prolonged seizures begin to emerge in the second year of life. Individuals with Dravet syndrome are also at higher risk of febrile seizures, prolonged status epilepticus, and of SUDEP (sudden unexplained death in epilepsy) and have a wide range of associated conditions, which all need to be properly treated and managed. Dravet syndrome is now considered a channelopathy with mutations in the gene encoding the α1 subunit (Na v 1.1) of the voltage-gated sodium channel (SCN1A) being one of the most common causes for the condition (1). A genetic change in SCN1A will present according to its severity, the genetic background of the patient and environmental factors; those factors in turn will determine the clinical presentation of Dravet syndrome. While Dravet syndrome is largely refractory to common antiepileptic drugs, ketogenic diet therapy has recently been used for the management of Dravet syndrome and related severe myoclonic epilepsies (2), and in one study, 65 percent of patients with Dravet syndrome treated with the ketogenic diet experienced a greater than 50 percent reduction in seizure frequency (3). To study pathophysiological mechanisms implicated in Dravet syndrome and develop improved treatment options for the condition, several features of the syndrome have been reproduced by creating mice engineered with a SCN1A gene mutation (mSCN1A) (4). Animals homozygous for the mutation develop seizures as early as 18 days after birth, and initial mechanistic studies suggested that Nav1.1 plays critical roles in the spike output from parvalbumin-positive interneurons and that altered functions of these inhibitory circuits may contribute to epileptic seizures in the mutant animals (4). The study by Gu et al. was designed to further characterize mechanisms of circuit excitability in mSCN1A mice and to test possible therapeutic interventions. The authors used hippocampal slice preparations from juvenile mSCN1A mice and employed a combination of extracellular and whole-cell voltage clamp studies with fast voltage-sensitive dye imaging (VSDI). VSDI is a functional imaging technique that uses voltage sensitive dies to study cortical dynamics at high spatial OBJECTIVE: Severe myoclonic epilepsy in infancy (SMEI) or Dravet syndrome is one of the most devastating childhood epilepsies. Children with SMEI have febrile and afebrile seizures (FS …