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

• Published in: Channels (Austin, Tex.) Tex.), 2013-11, Vol.7 (6), p.468-472
• Main Authors: Cheah, Christine S, Westenbroek, Ruth E, Roden, William H, Kalume, Franck, Oakley, John C, Jansen, Laura A, Catterall, William A
• Format: Article
• Language: English
• Subjects: Animals; Brain - growth & development; Brain - metabolism; Death, Sudden; Epilepsies, Myoclonic - metabolism; Gene Expression Regulation; Humans; Mice; NAV1.1 Voltage-Gated Sodium Channel - metabolism; NAV1.3 Voltage-Gated Sodium Channel - metabolism; Short Communication; Sodium Channels - metabolism; Time Factors
• ISSN: 1933-6950; 1933-6969
• DOI: 10.4161/chan.26023

Dravet Syndrome (DS) is an intractable genetic epilepsy caused by loss-of-function mutations in SCN1A, the gene encoding brain sodium channel Nav 1.1. 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 Nav 1.3 and the rise in expression of the adult sodium channel Nav 1.1 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 Nav 1.3 and increase in Nav 1.1 with age. In light of these results, we introduce the hypothesis that the natural loss Nav 1.3 channel expression in brain development, coupled with the failure of increase in functional Nav 1.1 channels in DS, defines a tipping point that leads to disinhibition of neural circuits, intractable seizures, co-morbidities, and premature death in this disease.