Hippocampal deletion of Na_V1.1 channels in mice causes thermal seizures and cognitive deficit characteristic of Dravet Syndrome.

Abstract

Dravet Syndrome is a severe childhood epileptic disorder caused by haploinsufficiency of the <i>SCN1A</i> gene encoding brain voltage-gated sodium channel Na_V1.1. Symptoms include treatment-refractory epilepsy, cognitive impairment, autistic-like behavior, and premature death. The specific loci of Na_V1.1 function in the brain that underlie these global deficits remain unknown. Here we specifically deleted <i>Scn1a</i> in the hippocampus using the Cre-Lox method in weanling mice. Local gene deletion caused selective reduction of inhibitory neurotransmission measured in dentate granule cells. Mice with local Na_V1.1 reduction had thermally evoked seizures and spatial learning deficits, but they did not have abnormalities of locomotor activity or social interaction. Our results show that local gene deletion in the hippocampus can induce two of the most severe dysfunctions of Dravet Syndrome: Epilepsy and cognitive deficit. Considering these results, the hippocampus may be a potential target for future gene therapy for Dravet Syndrome.