SCN8A: When Neurons Are So Excited, They Just Can't Hide It.

SCN8A: When Neurons Are So Excited, They Just Can't Hide It. Epilepsy Curr. 2019 Jul 09;:1535759719858338 Authors: Gertler TS, Carvill GL Abstract Neuronal Mechanisms of Mutations in SCN8A Causing Epilepsy or Intellectual Disability Liu Y, Schubert J, Sonnenberg L, Helbig KL, Hoei-Hansen CE, Koko M, Rannap M, Lauxmann S, Huq M, Schneider MC, Johannesen KM, Kurlemann G, Gardella E7, Becker F, Weber YG, Benda J, Møller RS, Lerche H. Brain. 2019;142(2):376-390. doi:10.1093/brain/awy326. De novo mutations of the sodium channel gene SCN8A result in an epileptic encephalopathy with refractory seizures, developmental delay, and elevated risk of sudden death. p.Arg1872Trp is a recurrent de novo SCN8A mutation reported in 14 unrelated individuals with epileptic encephalopathy that included seizure onset in the prenatal or infantile period and severe verbal and ambulatory comorbidities. The major biophysical effect of the mutation was previously shown to be impaired channel inactivation accompanied by increased current density. We have generated a conditional mouse mutation in which expression of this severe gain-of-function mutation is dependent upon Cre recombinase. Global activation of p.Arg1872Trp by EIIa-Cre resulted in convulsive seizures and lethality at 2 weeks of age. Neural activation of the p.Arg1872Trp mutation by Nestin-Cre also resulted in early-onset seizures and death. Restriction of p.Arg1872Trp expression to excitatory neuro...
Source: Epilepsy Currents - Category: Neurology Tags: Epilepsy Curr Source Type: research