Spinal cord pathology in a Dravet Syndrome mouse model

Abstract

AbstractSummaryObjectivesDravet syndrome is a severe epileptic encephalopathy that begins in early childhood. More than 80% of patients with Dravet syndrome exhibit a haploinsufficiency inSCN1A, which encodes the voltage-gated sodium ion channel NaV1.1. The epilepsy is believed be caused by specific deficit ofSCN1Ain inhibitory interneurons of the hippocampus. However, the aetiology of other symptoms including gait disturbances, ataxia, cardiac issues and dysautonomia is less clear.MethodsIn anScn1aknock-out (Scn1a-/-) mouse model which recapitulates clinical phenotypes, we assessed NaV1.1 and neuroinflammation throughout the central nervous system.ResultsConsistent with current understanding, wild-type expression of NaV1.1 transcript and protein were absent in knock-out mice in the prefrontal cortex, striatum, hippocampus, thalamus, and cerebellum. Increased GFAP was detected in the brain only in the hippocampus. Transcript and protein were detected in wild-type cervical, thoracic and lumbar spinal cord but not in knock-out mice. Unexpectedly, GFAP was increased in all three spinal regions. Therefore, we proceeded to perform transcriptomic analysis of cortex, hippocampus and spinal cord. Pathways associated with monooxygenase activity, fatty acid ligases and lactate transporters were highly dysregulated in the spinal cord.ConclusionThe existence and relevance of pathology of the spinal cord in Dravet syndrome has received scant attention. Our findings are consistent with some systemic symptoms of Dravet syndrome, with the benefits of treatments which may modulate the astrocyte-neuron lactate shuttle such as Stiripentol and ketogenic dietary regimes, and with the efficacy of intrathecal delivery of therapeutics.Key PointsDecrease of endogenousScn1aand NaV1.1 expression inScn1a-/-mice has a widespread impact on the gene expression profile in the spinal cord.Increased GFAP expression observed in the spinal cord ofScn1a-/-mice.Differentially expressed genes related to monooxygenase activity, fatty acid ligases and lactate transporters in cervical spinal cord ofScn1a-/-mice.