syndrome specific models of human epilepsy

Syndrome specific models of epilepsy are the key to understanding the fundamental origins of this disease and to the development of better therapeutic treatments.  The goal of this project is to develop genetically modified mouse models of specific human epilepsy syndromes.  These studies begin with the function validation of epilepsy causing gene mutations found in patient populations a collaborative team led by Prof Sam Berkovic.  The majority of these mutations are found in a class of proteins called ion channels.  These membrane spanning proteins create gated switches in neurons, control excitability of neurons and underlie the basic functioning of the brain.  We assess the effects of mutations by using patch clamp electrophysiology, two electrode voltage clamp and a range of cell biological methods.  Once disease causing mutations are identified in human studies, mouse models are created that harbour the identical mutations.  Validation of these models requires detailed study at the molecular, neuronal, network and whole animal level.  We search for similarities in cellular behaviour and seizure activity between our mice and the patients with the mutation as this provides us with greater confidence that fundamental mechanisms of seizure genesis may be shared.  Our search for the mechanism of epileptogenesis requires the use of miniaturised single neuron recording devices for use in unrestrained and awake animals as well as use of in vivo patch clamp recordings in anesthetised mice.  We couple these studies with EEG and behavioural tests as our markers of syndrome type.  We have used molecular biological methods to engineer switching of gene mutations on and off in living mice to investigate the study of direct versus developmental effects of mutations.  We envisage that a range of different models will have to be created to cover the major refractory epilepsies seen in man.  One major activity is the phenotypic characterisation of each of these three models.  With these models in hand our studies should reveal mechanisms of seizure genesis, thus providing fertile ground for development of novel therapeutics.