Hippocampal deletion of Na V 1.1 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 SCN1A 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 Scn1a 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. Significance Dravet Syndrome is an intractable epileptic disorder that includes cognitive and social-interaction deficits. It is caused by loss-of-function mutations in the brain sodium channel Na_V1.1. We asked whether symptoms of Dravet Syndrome could be induced by introducing the mutation only in the hippocampus, a brain region important for learning and memory and for control of brain excitability. Local mutation of Na_V1.1 specifically reduced the excitability of inhibitory neurons in the hippocampus. This local mutation caused thermally evoked seizures and spatial learning deficits, which are brain-wide effects. Our results point to a key role for the hippocampus in generating epilepsy and cognitive deficit in Dravet Syndrome and suggest that gene therapy targeting the hippocampus might be effective in this devastating disease.