Stargazin and AMPA receptor expression at cortical synapses in epileptic rats

Research Opportunity
PhD, Masters by Research, Honours
Project Status
Future
Department
Medicine and Radiology
Location
Royal Melbourne Hospital
Supervisor Email Number Webpage
Dr Kim Powell kpowell@unimelb.edu.au +61 3 9035 6394 Personal web page
Dr Pablo Casillas-Espinosa pablo.casillas@unimelb.edu.au Personal web page

Project Details

Absence seizures, one of the most common seizure types in humans with idiopathic generalised epilepsy (IGE), 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 are 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 how they interact to result in epilepsy remains to be determined. GAERS are a strain of rats which spontaneously develop generalized absence seizures. AMPA receptors are ionotropic transmembrane receptors for the excitatory neurotransmitter glutamate, which mediates fast synaptic transmission in the central nervous system. Stargazin is the archetypal member of a family of proteins called Transmembrane AMPA Receptor regulatory Proteins (TARPs), and is critical for the trafficking and anchoring of AMPA receptors to synaptic membranes. Stargazin also influences electrophysiological properties of AMPA receptors including the slowing of deactivation and reducing desensitization rates.

This newly identified TARP role for stargazin may have major functional implications on the homeostatic balance of neuronal excitation, and potentially for the pathophysiology of epilepsy. Recent work from our lab has shown increased expression of stargazin at neuronal membranes in the somatosensory cortex of epileptic GAERS animals, a brain region thought to be involved in the generation of absence seizures. These animals also show increased membrane AMPA receptor expression, which may be driven by elevated stargazin levels. Stargazin is known to interact with other synaptic proteins to localise AMPA receptors to the post-synaptic density (PSD), the region of the postsynapse opposite sites of neurotransmitter release.

The specific aims of this project are * To biochemically isolate the PSD from the somatosensory cortex of epileptic GAERS and non-epileptic control (NEC) rats * To compare PSD localization of stargazin, AMPA receptor subunits and other synaptic proteins in GAERS and NECs * To correlate membrane and synaptic expression of stargazin and AMPA receptors with seizure parameters

Skills

The skills expected to be learnt from this project include: Small animal handling and neurosurgery (electrode implantations), EEG recordings and analysis, and biochemical and molecular analysis (subcellular fractionation, western blotting).



Faculty Research Themes

Neuroscience

School Research Themes

Neuroscience & Psychiatry



Research Opportunities

PhD, Masters by Research, Honours Graduate Research Students who are interested in joining this project will need to consider their elegibility as well as other Graduate Research requirements before contacting the supervisor of this research

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Key Contact

For further information about this research, please contact a supervisor.

Department

Medicine and Radiology

Research Group / Unit / Centre

Molecular Epilepsy

Research Node

Royal Melbourne Hospital