Kindling Dravet Syndrome Symptoms from the Hippocampus

Abstract

Dravet Syndrome is an epileptic condition with varied comorbidities caused by haploinsufficiency of the Scn1a gene, which encodes the alpha-1 subunit of the NaV1.1 sodium channel. Dravet Syndrome is characterized by treatment-refractory epileptic seizures that present at an early age, followed by other comorbidities such as autism and cognitive impairment. The mouse model of Dravet Syndrome closely mirrors the mutations and phenotypes present in the human population, which result from hypoexcitability of forebrain GABAergic interneuron populations due to reduced sodium current after loss-of-function in NaV1.1 channels. However, the region-specific impact of reduced Nav1.1 expression on epileptiform activity and Dravet symptoms has been unknown. We hypothesized that decreased interneuron activity which results in increased excitability and dysregulation in distinct and varied brain regions is responsible for the phenotypes of Dravet Syndrome. Through a series of genetic, physiological, and behavioral experiments, we have identified the hippocampus as a critical region in which loss-of-function of Nav1.1 channels contributes to the symptoms of Dravet Syndrome. These studies have increased our understanding of the molecular mechanisms behind the disease and has revealed anatomical targets for pharmacological management.