Altered gene expression profile in a mouse model of SCN8A encephalopathy

Ryan S. Sprissler, Jacy L. Wagnon, Rosie K. Bunton-Stasyshyn, Miriam H. Meisler, Michael F. Hammer

Research output: Research - peer-reviewArticle

  • 2 Citations

Abstract

SCN8A encephalopathy is a severe, early-onset epilepsy disorder resulting from de novo gain-of-function mutations in the voltage-gated sodium channel Nav1.6. To identify the effects of this disorder on mRNA expression, RNA-seq was performed on brain tissue from a knock-in mouse expressing the patient mutation p.Asn1768Asp (N1768D). RNA was isolated from forebrain, cerebellum, and brainstem both before and after seizure onset, and from age-matched wildtype littermates. Altered transcript profiles were observed only in forebrain and only after seizures. The abundance of 50 transcripts increased more than 3-fold and 15 transcripts decreased more than 3-fold after seizures. The elevated transcripts included two anti-convulsant neuropeptides and more than a dozen genes involved in reactive astrocytosis and response to neuronal damage. There was no change in the level of transcripts encoding other voltage-gated sodium, potassium or calcium channels. Reactive astrocytosis was observed in the hippocampus of mutant mice after seizures. There is considerable overlap between the genes affected in this genetic model of epilepsy and those altered by chemically induced seizures, traumatic brain injury, ischemia, and inflammation. The data support the view that gain-of-function mutations of SCN8A lead to pathogenic alterations in brain function contributing to encephalopathy.

LanguageEnglish (US)
Pages134-141
Number of pages8
JournalExperimental Neurology
Volume288
DOIs
StatePublished - Feb 1 2017

Fingerprint

Brain Diseases
Transcriptome
Seizures
Mutation
Voltage-Gated Sodium Channels
Gliosis
Prosencephalon
Epilepsy
RNA
Brain
Genes
Voltage-Gated Potassium Channels
Convulsants
Genetic Models
Encephalitis
Calcium Channels
Neuropeptides
Brain Ischemia
Age of Onset
Cerebellum

Keywords

  • Astrocyte
  • Epileptic encephalopathy
  • Gene expression
  • RNA-seq
  • Seizure
  • Sodium channel
  • Transcriptome

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

Cite this

Sprissler, R. S., Wagnon, J. L., Bunton-Stasyshyn, R. K., Meisler, M. H., & Hammer, M. F. (2017). Altered gene expression profile in a mouse model of SCN8A encephalopathy. Experimental Neurology, 288, 134-141. DOI: 10.1016/j.expneurol.2016.11.002

Altered gene expression profile in a mouse model of SCN8A encephalopathy. / Sprissler, Ryan S.; Wagnon, Jacy L.; Bunton-Stasyshyn, Rosie K.; Meisler, Miriam H.; Hammer, Michael F.

In: Experimental Neurology, Vol. 288, 01.02.2017, p. 134-141.

Research output: Research - peer-reviewArticle

Sprissler, RS, Wagnon, JL, Bunton-Stasyshyn, RK, Meisler, MH & Hammer, MF 2017, 'Altered gene expression profile in a mouse model of SCN8A encephalopathy' Experimental Neurology, vol 288, pp. 134-141. DOI: 10.1016/j.expneurol.2016.11.002
Sprissler RS, Wagnon JL, Bunton-Stasyshyn RK, Meisler MH, Hammer MF. Altered gene expression profile in a mouse model of SCN8A encephalopathy. Experimental Neurology. 2017 Feb 1;288:134-141. Available from, DOI: 10.1016/j.expneurol.2016.11.002
Sprissler, Ryan S. ; Wagnon, Jacy L. ; Bunton-Stasyshyn, Rosie K. ; Meisler, Miriam H. ; Hammer, Michael F./ Altered gene expression profile in a mouse model of SCN8A encephalopathy. In: Experimental Neurology. 2017 ; Vol. 288. pp. 134-141
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