Prominent role of forebrain excitatory neurons in SCN8A encephalopathy

Mutations in neuronal sodium channels cause neurodevelopmental disorders and epilepsy. Bunton-Stasyshyn et al. develop a mouse model with conditional expression of the recurrent gain-of-function mutation SCN8A-R1872W. Activation by Cre recombinase in excitatory but not inhibitory neurons results in...

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Published in:	Brain (London, England : 1878) Vol. 142; no. 2; pp. 362 - 375
Main Authors:	Bunton-Stasyshyn, Rosie K A, Wagnon, Jacy L, Wengert, Eric R, Barker, Bryan S, Faulkner, Alexa, Wagley, Pravin K, Bhatia, Kritika, Jones, Julie M, Maniaci, Marissa R, Parent, Jack M, Goodkin, Howard P, Patel, Manoj K, Meisler, Miriam H
Format:	Journal Article
Language:	English
Published:	England Oxford University Press 01-02-2019
Subjects:	Animals Brain Diseases - genetics Brain Diseases - pathology Cells, Cultured Excitatory Postsynaptic Potentials - physiology Female Gain of Function Mutation - genetics Integrases - genetics Integrases - metabolism Male Mice Mice, Inbred C57BL Mice, Transgenic NAV1.6 Voltage-Gated Sodium Channel - genetics Neurons - pathology Neurons - physiology Organ Culture Techniques Original Prosencephalon - pathology Prosencephalon - physiology conditional allele 1.6 Na sodium channel mouse model epileptic encephalopathy
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Summary:	Mutations in neuronal sodium channels cause neurodevelopmental disorders and epilepsy. Bunton-Stasyshyn et al. develop a mouse model with conditional expression of the recurrent gain-of-function mutation SCN8A-R1872W. Activation by Cre recombinase in excitatory but not inhibitory neurons results in seizures and lethality, while activation in adult brain recapitulates the seizure disorder. Abstract 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 neurons using Emx1-Cre recapitulated seizures and juvenile lethality between 1 and 2 months of age. In contrast, activation of p.Arg1872Trp in inhibitory neurons by Gad2-Cre or Dlx5/6-Cre did not induce seizures or overt neurological dysfunction. The sodium channel modulator GS967/Prax330 prolonged survival of mice with global expression of R1872W and also modulated the activity of the mutant channel in transfected cells. Activation of the p.Arg1872Trp mutation in adult mice was sufficient to generate seizures and death, indicating that successful therapy will require lifelong treatment. These findings provide insight into the pathogenic mechanism of this gain-of-function mutation of SCN8A and identify excitatory neurons as critical targets for therapeutic intervention.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Rosie K.A. Bunton-Stasyshyn and Jacy L. Wagnon authors contributed equally to this work.
ISSN:	0006-8950 1460-2156
DOI:	10.1093/brain/awy324