Gene expression profiling in a mouse model of Dravet syndrome

Nicole Alise Hawkins, Jeffrey D. Calhoun, Alexandra M. Huffman, Jennifer A Kearney

Research output: Contribution to journalArticle

Abstract

Dravet syndrome is a severe, early-onset epileptic encephalopathy frequently resulting from de novo mutations of SCN1A. Mice with heterozygous deletion of Scn1a (Scn1a+/−) model many features of Dravet syndrome, including spontaneous seizures and premature lethality. Scn1a+/− mice exhibit variable phenotype penetrance and expressivity dependent upon the strain background. On the 129S6/SvEvTac (129) strain, Scn1a+/− mice do not display an overt phenotype. However Scn1a+/− mice on the [129S6xB6]F1 strain (F1.Scn1a+/−) exhibit juvenile-onset spontaneous seizures and premature lethality. QTL mapping identified several modifier loci responsible for strain-dependent differences in survival of Scn1a+/− mice, but these loci do not account for all the observed phenotypic variance. Global RNA-seq analysis was performed to identify additional genes and pathways that may contribute to variable phenotypes. Hippocampal gene expression was analyzed in wild-type (WT) and Scn1a+/− mice on both F1 and 129 strains, at two time points during disease development. There were few gene expression differences between 129.WT and 129.Scn1a+/− mice and approximately 100 genes with small expression differences (6–36%) between F1.WT and F1.Scn1a+/− mice. Strain-specific gene expression differences were more pronounced, with dozens of genes with >1.5-fold expression differences between 129 and F1 strains. Age-specific and seizure-related gene expression differences were most prominent, with hundreds of genes with >2-fold differences in expression identified between groups with and without seizures, suggesting potential differences in developmental trajectory and/or homeostatic plasticity during disease onset. Global expression differences in the context of Scn1a deletion may account for strain-dependent variation in seizure susceptibility and survival observed in Scn1a+/− mice.

LanguageEnglish (US)
Pages247-256
Number of pages10
JournalExperimental Neurology
Volume311
DOIs
StatePublished - Jan 1 2019

Fingerprint

Myoclonic Epilepsy
Gene Expression Profiling
Seizures
Gene Expression
Phenotype
Genes
129 Strain Mouse
Penetrance
Brain Diseases
RNA
Mutation

Keywords

  • Epilepsy
  • Epileptic encephalopathy
  • Gene expression
  • RNA-seq
  • Seizure
  • Voltage-gated sodium channel

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

Cite this

Hawkins, Nicole Alise ; Calhoun, Jeffrey D. ; Huffman, Alexandra M. ; Kearney, Jennifer A. / Gene expression profiling in a mouse model of Dravet syndrome. In: Experimental Neurology. 2019 ; Vol. 311. pp. 247-256.
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Gene expression profiling in a mouse model of Dravet syndrome. / Hawkins, Nicole Alise; Calhoun, Jeffrey D.; Huffman, Alexandra M.; Kearney, Jennifer A.

In: Experimental Neurology, Vol. 311, 01.01.2019, p. 247-256.

Research output: Contribution to journalArticle

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