Action of Nav1.6 and Nav1.2-Specific Sodium Channel Blockers on Seizures in a Mouse Model of Pediatric Epilepsy

Dravet syndrome (DS) is caused by mutations in a specific type of protein called a sodium channel, and specifically, a protein called Nav1.1. These mutations impair the function of inhibitory neurons and alter the balance of excitation to inhibition, in favor of excitation. Many of the symptoms of DS are replicated in a genetic mouse model of the syndrome including thermally-induced seizures, spontaneous seizures, premature death, hyperactivity, severe cognitive impairment, and autistic-like behaviors.

Using their genetic mouse model of DS, Dr. Westenbroek’s lab plans to test newly developed inhibitors that act on sodium channels called Nav1.6 and Nav1.2. These drugs may be beneficial over traditional sodium channel blockers with fewer side effects because they would specifically block sodium channels in excitatory neurons and improve the excitation-inhibition imbalance. With this grant, Dr. Westenbroek’s team will test these drugs for efficacy on specific symptoms of DS such as thermally induced seizures, spontaneous seizures, and premature death. If these findings are validated, they could transform treatment of pediatric epilepsies by permitting development of improved therapeutic strategies for control of intractable seizures.