Epilepsy Research Group, Clinical and Health Sciences, Australian Centre for Precision Health, University of South Australia, Adelaide, SA, 5000, Australia.
Pharmacy, School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, 3083, Australia.
Sci Rep. 2024 Feb 9;14(1):3357. doi: 10.1038/s41598-024-53588-x.
Mutations in the KCNT1 potassium channel cause severe forms of epilepsy which are poorly controlled with current treatments. In vitro studies have shown that KCNT1-epilepsy mutations are gain of function, significantly increasing K current amplitudes. To investigate if Drosophila can be used to model human KCNT1 epilepsy, we generated Drosophila melanogaster lines carrying human KCNT1 with the patient mutation G288S, R398Q or R928C. Expression of each mutant channel in GABAergic neurons gave a seizure phenotype which responded either positively or negatively to 5 frontline epilepsy drugs most commonly administered to patients with KCNT1-epilepsy, often with little or no improvement of seizures. Cannabidiol showed the greatest reduction of the seizure phenotype while some drugs increased the seizure phenotype. Our study shows that Drosophila has the potential to model human KCNT1- epilepsy and can be used as a tool to assess new treatments for KCNT1- epilepsy.
KCNT1 钾通道突变导致严重的癫痫，目前的治疗方法对此类癫痫的控制效果不佳。体外研究表明，KCNT1 癫痫突变是功能获得性的，显著增加了 K 电流幅度。为了研究果蝇是否可用于模拟人类 KCNT1 癫痫，我们生成了携带人类 KCNT1 突变 G288S、R398Q 或 R928C 的果蝇品系。在 GABA 能神经元中表达每种突变通道都会引起癫痫表型，这些表型对最常用于治疗 KCNT1 癫痫患者的 5 种一线抗癫痫药物的反应要么是阳性，要么是阴性，往往对癫痫发作的改善很小或没有。大麻二酚显示出对癫痫表型最大的降低作用，而一些药物则增加了癫痫表型。我们的研究表明，果蝇有可能模拟人类 KCNT1 癫痫，可作为评估治疗 KCNT1 癫痫新疗法的工具。
