Kim PowellKim Powell

Recipient of the 2008 Molly McDonnell Foundation Scholarship

Department of Medicine, Royal Melbourne Hospital, The University of Melbourne

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 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 how they interact to result in epilepsy remains to be determined.

AMPA receptors are ionotropic transmembrane receptors for the excitatory neurotransmitter, glutamate that mediates fast synaptic transmission in the central nervous system. Stargazin, a member of a new family of proteins called Transmembrane AMPA Receptor regulatory Proteins (TARPs), is critical for the trafficking and anchoring of AMPA receptors to synaptic membranes, leading to the designation of a new family of proteins termed. 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. Indeed research from our laboratory using a genetic animal model has linked an increase in stargazin expression in the brain to absence epilepsy. Associated with an increase in stargazin expression is an increase in AMPA receptor expression only at the plasma membrane. This would be expected to enhance neuronal excitability and therefore be potentially pro-epileptic. I am continuing this line of research in the hope of providing more information regarding stargazin’s and AMPA receptor contribution to absence epilepsy.

Kim Powell

Kim Powell acknowledges The Molly McDonnell Foundation in the following publications:

Powell, K.L., Cain, S.M., Ng, C., Sirdesai, S., David, L.S., Kyi, M., Garcia, E., Tyson, J.R., Reid, C.A., Bahlo, M., Foote, S.J., Snutch, T.P., O'Brien, T.J (2009). A Cav3.2 T-type calcium channel point mutation has splice-variant-specific effects on function and segregates with seizure expression in a polygenic rat model of absence epilepsyThe Journal of Neuroscience, 29(2), 371–380.

Powell, K.L., Ng, C., O'Brien, T.J., Xu, S.H., Williams, D.A., Foote, S.J., Reid, C.A. (2008). Decreases in HCN mRNA expression in the hippocampus after kindling and status epilepticus in adult rats.Epilepsia, 49(10), 1686-95.

Powell, K.L., Kyi, M., Reid, C.A., Paradiso, L., D'Abaco, G.M., Kaye, A.H., Foote, S.J., O'Brien, T.J. (2008). Genetic absence epilepsy rats from Strasbourg have increased corticothalamic expression of stargazinNeurobiology of Disease, 31, 261–265.

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