Genetic epilepsy: identifying mechanisms and potential drug treatments, from nematodes to humans

Epilepsy is a common neurological disorder that has a major impact on patient mortality, morbidity and quality of life. Clinical management remains extremely problematic, held back both by diagnostic and treatment limitations. Around 40% of cases are considered to be "genetic epilepsy" (~250,000 people in UK), but often, the identity of the genes involved eludes us. However, a recent landmark paper has identified mis-sense mutations in GABAA receptors as a common cause of genetic epilepsy (Lancet Neurology (2018) 17, 699). This presents a timely opportunity to understand how these mutations in GABAA receptors lead to epilepsy and to translate this knowledge into much needed new therapies (around 1/3 of epileptics are resistant to current medication).

Our novel project combines the simple molecular genetics of C. elegans with the translational power of electrophysiological recording from mammalian neurons, to identify potential new antiepileptic drugs. This capitalises on the different expertise of the supervisory team in C. elegans disease models (Morgan) and rodent and human brain slice electrophysiology (Trevelyan, Ilie).

The Morgan lab recently published that loss-of-function mutations in the unc-49 GABAA receptor cause seizure-like behaviour in C. elegans and that this model can be used to screen for anti-epileptic drugs. In this project, we will rescue these unc-49 worms by expressing either wild type or epilepsy-associated human mutant GABAA receptors. This simple method will identify mutations that impair human GABAA receptor function, since these will be less effective at rescuing the unc-49 seizure phenotype. Worms expressing defective GABAA receptors responses will then be screened using known GABAergic drugs and novel compounds to identify potential new treatments.

The project will test the efficacy of these identified candidate drugs in simple assays of cortical network function perfected by Trevelyan and Ilie, using rodent and human brain slices. These assays have been developed from extensive in vitro studies, that have been validated as representative of the activity patterns also seen in vivo, of spontaneous, medically-refractory epilepsy in humans. This work will rigorously test the translational potential of candidate drugs, thereby priming future clinical trials. Importantly, this Studentship will provide unique research training in epileptology, using state-of-the-art techniques in molecular genetics, pharmacology and electrophysiology, and giving experience in model systems ranging from nematode worms through rodents to the human brain.