Increased persistent Na+ current contributes to seizure in the slamdance bang-sensitive Drosophila mutant
Increased persistent Na+ current contributes to seizure in the slamdance bang-sensitive Drosophila mutant
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DOI：
10.1152/jn.00808.2010
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发表时间：
2011-07-01
影响因子：
2.5
通讯作者：
Baines, Richard A.
中科院分区：
文献类型：
--
作者：
Marley, Richard;Baines, Richard A.
马利·R，贝恩斯·R。持续增加的Na+电流有助于在slamdance bang敏感的果蝇突变体中癫痫发作。中国生物医学工程学报（英文版），2009,31(4):557 - 557。首次发表于2011年3月30日；doi: 10.1152 / jn.00808.2010。-临床需要扩大对癫痫的认识，并找到治疗这种疾病的新方法。Bang-sensitive （bs）果蝇突变体，表现出癫痫发作阈值降低，提供了一个有吸引力的可能性，结合了易处理的遗传学，电生理学和高通量筛选。然而，尽管有这些优势，导致癫痫发作的确切电生理异常尚未在任何bs突变体中确定。正因为如此，果蝇作为临床前模型的适用性尚未建立。在这项研究中，我们发现电击bs slamdance （sda）幼虫足以诱导长时间的癫痫样发作。来自已识别的运动神经元（称为aCC和RP2）的全细胞电压钳记录显示突触电流在振幅和持续时间上都大大增加。电流钳记录表明，这些输入产生了更长的平台去极化，并增加了这些细胞的动作电位放电。对一龄和三龄幼虫运动神经元电压门控电流的分析显示，一龄幼虫持续增加的Na+电流（I-Nap）和减少的Ca2 +电流（+），而这在年龄较大的三龄幼虫中是正常的。通过观察发现，给sda幼虫喂食足以减少I-Nap的抗癫痫药物苯妥英（phenytoin），可以挽救癫痫样发作持续时间和运动神经元的突触兴奋，从而表明I-Nap的增加可能有助于癫痫样活动。相比之下，给野生型幼虫喂食海葵毒素（一种优先增加I-Nap的药物）或苯妥英（phenytoin）都足以诱导bs行为表型。最后，我们发现，给怀孕的sda雌性喂食苯妥英足以减少I-Nap和突触电流，并挽救其幼虫后代的bs表型，这表明癫痫发作的易感性可能是胚胎神经发育异常的结果。
Marley R, Baines RA. Increased persistent Na+ current contributes to seizure in the slamdance bang-sensitive Drosophila mutant. J Neurophysiol 106: 18-29, 2011. First published March 30, 2011; doi:10.1152/jn.00808.2010.-There is clinical need to extend the understanding of epilepsy and to find novel approaches to treat this condition. Bang-sensitive (bs) Drosophila mutants, which exhibit reduced thresholds for seizure, offer an attractive possibility to combine tractable genetics, electrophysiology, and high-throughput screening. However, despite these advantages, the precise electrophysiological aberrations that contribute to seizure have not been identified in any bs mutant. Because of this, the applicability of Drosophila as a preclinical model has not yet been established. In this study, we show that electroshock of bs slamdance (sda) larvae was sufficient to induce extended seizure-like episodes. Whole cell voltage-clamp recordings from identified motoneurons (termed aCC and RP2) showed synaptic currents that were greatly increased in both amplitude and duration. Current-clamp recordings indicated that these inputs produced longer-lived plateau depolarizations and increased action potential firing in these cells. An analysis of voltage-gated currents in these motoneurons, in both first and third instar larvae, revealed a consistently increased persistent Na+ current (I-Nap) and a reduced Ca2(+) current in first instar larvae, which appeared normal in older third instar larvae. That increased I-Nap may contribute to seizure-like activity is indicated by the observation that feeding sda larvae the antiepileptic drug phenytoin, which was sufficient to reduce I-Nap, rescued both seizure-like episode duration and synaptic excitation of motoneurons. In contrast, feeding of either anemone toxin, a drug that preferentially increases I-Nap, or phenytoin to wild-type larvae was sufficient to induce a bs behavioral phenotype. Finally, we show that feeding of phenytoin to gravid sda females was sufficient to both reduce I-Nap and synaptic currents and rescue the bs phenotype in their larval progeny, indicating that a heightened predisposition to seizure may arise as a consequence of abnormal embryonic neural development.