PDF(Pubmed)
Abstract：
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.
摘要：
KCNT1钾通道中的突变引起严重形式的癫痫,其在目前的治疗中控制不良。体外研究表明，KCNT1-癫痫突变是功能的获得，显着增加K+电流幅度。为了研究果蝇是否可以用来模拟人类KCNT1癫痫，我们产生了带有患者突变G288S的人类KCNT1的果蝇系，R398Q或R928C。GABA能神经元中每个突变通道的表达产生了癫痫发作表型，该表型对最常用于KCNT1癫痫患者的5种前线癫痫药物产生了积极或消极的反应。通常癫痫发作很少或没有改善。大麻二酚显示癫痫发作表型的最大减少，而某些药物增加了癫痫发作表型。我们的研究表明，果蝇具有模拟人类KCNT1-癫痫的潜力，可以用作评估KCNT1-癫痫新疗法的工具。
