Correlations in timing of sodium channel expression, epilepsy, and sudden death in Dravet syndrome

Dravet Syndrome (DS) is an intractable genetic epilepsy caused by loss-of-function mutations in SCN1A, the gene encoding brain sodium channel Na_v1.1. DS is associated with increased frequency of sudden unexpected death in humans and in a mouse genetic model of this disease. Here we correlate the time course of declining expression of the murine embryonic sodium channel Na_v1.3 and the rise in expression of the adult sodium channel Na_v1.1 with susceptibility to epileptic seizures and increased incidence of sudden death in DS mice. Parallel studies with unaffected human brain tissue demonstrate similar decline in Na_v1.3 and increase in Na_v1.1 with age. In light of these results, we introduce the hypothesis that the natural loss Na_v1.3 channel expression in brain development, coupled with the failure of increase in functional Na _v1.1 channels in DS, defines a tipping point that leads to disinhibition of neural circuits, intractable seizures, co-morbidities, and premature death in this disease.