NIH awards Melbourne researcher US$1.7m

Melbourne University epilepsy investigator Dr Steve Petrou has received a prestigious National Institutes of Health grant to study what happens in the brain of a transgenic mouse that exhibits human-like epileptic seizures.

Petrou and his US co-worker Dr Matthew Jones, of the University of Madison, Wisconsin, will use their US$1.7 million grant to study how a mutation that causes a common, inherited form of epilepsy in humans sends brain function awry during seizures.

Last year Petrou, who divides his research time between Melbourne University's Department of Physiology and the Howard Florey Institute of Experimental Medicine, developed a 'knock-in' transgenic mouse with a mutation that disrupts the brain's electrical activity.

Petrou's mouse is the world's first animal model of an inherited human epilepsy. Jones is a GABA receptor expert -- the mutation in question affects the gamma sub-unit, one of the five 'modules' that assemble to form the receptor.

The mutation triggers temporary absence epilepsy -- commonly known as petit mal seizures -- in infancy, as well as generalised seizures during high fever. In adults, it results in a variety of generalized epilepsy syndromes that involve the entire brain; other epilepsies affect only certain regions of the brain.

They will make a detailed comparative analysis of the biophysics of the synapse in normal and knock in-mice, and correlate electrophysiological changes with behavioural changes in the mutant mouse.

"So far we've only studied the effect of the mutation in cultured cell lines," Petrou said. "We're now going to do a very detailed phenotypic analysis in brains, using new equipment we've developed."

Petrou has been working with Adelaide-based company Bionomics to develop the mouse model, as well as miniaturised electroencephalogram to monitor changing electrical activity in the mouse's brain before and during seizures.

The tiny four-channel instrument is light enough to be worn by the mouse as it freely moves around, instead of requiring it to be restrained within a Faraday cage. Petrou said it was important that the mouse was allowed to behave normally, so it exhibited normal brain activity.

Petrou said the project was aimed at determining the physiological basis of a common, clinically relevant form of epilepsy. Typically, the mutations involved in inherited epilepsies are quite rare, making it too expensive to develop novel drugs for specific forms of epilepsy, but importantly, the mouse model represents the physiology of common forms of human epilepsy.

He said an understanding of the mechanisms that trigger epileptic seizures, and the way seizures affect broader patterns of electrical activity across the brain, may reveal mechanisms common to rarer forms of epilepsy that could be targeted with generic drugs.