Modelling human KCNT1-epilepsy inDrosophila: a seizure phenotype and drug responses

Abstract

AbstractMutations in theKCNT1potassium channel cause severe forms of epilepsy which are resistant to current treatments.In vitrostudies have shown thatKCNT1-epilepsy mutations are gain of function, significantly increasing K+current amplitudes. To investigate ifDrosophilacan be used to model humanKCNT1epilepsy, we generatedDrosophila melanogasterlines carrying humanKCNT1with the patient mutation G288S, R398Q or R928C. Expression of each mutant channel in GABAergic neurons gave a seizure phenotype which was sensitive to drugs currently used to treat patients withKCNT1-epilepsy. Cannabidiol showed the greatest reduction of the seizure phenotype while some drugs increased the seizure phenotype. Our study shows thatDrosophilacan be used to model humanKCNT1-epilepsy and potentially used as a tool to assess new treatments forKCNT1epilepsy.