Investigating the role of a Cav3.2 calcium channel mutation in contributing to the epileptic phenotype using congenic rat strains and a knock in mouse model
Group LeaderDr Kim Powell
T: +61 3 9035 6394
Location: Department of Medicine, Melbourne Brain Centre
Absence seizures, one of the most common seizure types in humans with genetic generalised epilepsy (GGE), are generalised non-convulsive events characterised by recurrent episodes of staring with unresponsiveness. Absence seizures most commonly affect children and adolescents who can experience hundreds of seizures per day and if left untreated can lead to disruptions in learning. Despite the important recent identification of genetic mutations in some rare families with IGEs showing a monogenic inheritance, in the common situation (>95% of sufferers) with complex inheritance patterns, the genetic determinants of the absence seizures is still unknown. These epilepsies are presumed to be polygenic, with more than one genetic variation contributing to the phenotype, but the nature of these variations and the mechanisms by which they act to result in epilepsy remains to be determined. In an important, well characterised model of GGE with absence seizures, the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), our research group has discovered a homozygous, missense, single nucleotide (G to C) mutation in the Cav3.2 T-type calcium (Ca2+) channel gene (Cacna1h) resulting in an amino acid from arginine to proline (R1584P). The R1584P mutation correlates with the epileptic phenotype in GAERS doubled crossed with Non-Epileptic Control (NEC) rats. Additionally, the R1584P mutation increases the rate of recovery from channel inactivation in a splice variant specific manner, producing a predicted gain-of-function phenotype.
We have a knock-in mouse model of the R1584P Cav3.2 mutation as well as two congenic rat strains; a NEC strain expressing the R1584P mutation and a GAERS strain without the R1584P mutation which we will use as tools to investigate the neurobiological mechanisms by which the R1584P mutation results in is pro-absence effects. These experiments will explore further the specific role played by the R1584P mutation in the absence phenotype of GAERS and the effect of genetic background.
- Project 1: To examine the expression of spike-wave-discharges (SWD) in two different congenic rat strains, an NEC congenic strain expressing the R1584P mutation and a GAERS congenic rat strain without the R1584P mutation.
- Project 2: To characterise the epileptic phenotype of a knock-in mouse expressing the R1584P mutation and to investigate the effect of genetic background.
Skills: The skills expected to be learnt from this project include: Small animal handling and surgery, EEG recording and analysis.
- Pablo Casillas, Post-Doc
- Emma Braine, Research Assistant
This research project is available to PhD students to join as part of their thesis.
Please contact the Research Group Leader to discuss your options.
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