Spinal cord pathology in a Dravet Syndrome mouse model

Abstract Summary Objectives Dravet syndrome is a severe epileptic encephalopathy that begins in early childhood. More than 80% of patients with Dravet syndrome exhibit a haploinsufficiency in SCN1A , which encodes the voltage-gated sodium ion channel Na V 1.1. The epilepsy is believed be caused by specific deficit of SCN1A in inhibitory interneurons of the hippocampus. However, the aetiology of other symptoms including gait disturbances, ataxia, cardiac issues and dysautonomia is less clear. Methods In an Scn1a knock-out ( Scn1a -/- ) mouse model which recapitulates clinical phenotypes, we assessed Na V 1.1 and neuroinflammation throughout the central nervous system. Results Consistent with current understanding, wild-type expression of Na V 1.1 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. Conclusion The 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 Points Decrease of endogenous Scn1a and Na V 1.1 expression in Scn1a -/- mice has a widespread impact on the gene expression profile in the spinal cord. Increased GFAP expression observed in the spinal cord of Scn1a -/- mice. Differentially expressed genes related to monooxygenase activity, fatty acid ligases and lactate transporters in cervical spinal cord of Scn1a -/- mice.