| First Author | Hawkins NA | Year | 2019 |
| Journal | Exp Neurol | Volume | 311 |
| Pages | 247-256 | PubMed ID | 30347190 |
| Mgi Jnum | J:268153 | Mgi Id | MGI:6271083 |
| Doi | 10.1016/j.expneurol.2018.10.010 | Citation | Hawkins NA, et al. (2019) Gene expression profiling in a mouse model of Dravet syndrome. Exp Neurol 311:247-256 |
| abstractText | 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. |
