Role of GABAA-receptor mutations in idiopathic generalized epilepsy: a developmental study

Epilepsy comprises a family of neurological disorders, characterized by an unbalance between cerebral excitability and inhibition tipped toward excess excitability. Interestingly, genetic forms of rare familial epilepsy (i.e idiopathic generalized epilepsy, IGE) were associated to monogenic mutations in ion channels responsible for neuronal inhibition (i.e. γ aminobutyric acid A receptors, GABAARs). Biophysical studies in vitro demonstrated that these GABAAR mutations decrease the level of GABAergic transmission, thus neuronal inhibition. However, while the predicted decrease in cell inhibition in vivo would favor epileptic phenotypes, other realistic scenarios are possible. In fact, GABAergic transmission plays an instrumental role in physiological neuronal development, and familial IGE patients express non functional mutated GABAAR for life, thus also during brain development. Based on preliminary results obtained with sophisticate techniques in our lab, we hypothesize that part of familial IGE phenotypes are due to reduced early GABAergic transmission and consequent brain maldevelopment. To test this hypothesis, we will develop rat models of rare familial IGEs associated to mutated GABAAR, and evaluate brain development and its correlation to seizures propensity. We will also attempt rescuing both developmental defects and epileptic phenotypes by treating developing animals with drugs enhancing GABAergic transmission. The proposed studies will expand knowledge on the development of familial IGE, and may provide a window for therapeutic intervention before symptoms are overt. Furthermore, the rescue experiments might be a prelude to developing therapeutic agents that may in future prevent developmental defects in offsprings at-risk of familiar IGE by timely drug treatment. We feel that our project fully embraces Telethon's mission in promoting basic scientific research towards cure and prevention of rare monogenic diseases by founding Italian labs of excellence.