Is seizure a consequence of altered neural development?

人类癫痫的发病率是一个重大的临床问题，多达三分之一的患者对目前的药物治疗没有反应，这一事实加剧了这一问题。癫痫的病因多种多样，在许多情况下是未知的。然而，我们所知道的是，癫痫是由构成中枢神经系统的神经细胞功能不正常引起的。人的中枢神经系统由许多不同类型的神经细胞组成，这些细胞必须相互沟通。这些细胞的不同之处在于它们接触的目标、它们释放的信号化学物质（神经递质）以及它们能够激发电动作电位的方式——这是大脑信号传导的基础。最近的两项研究强调，一些癫痫可能是由于异常活动模式的发生而导致神经发育改变的结果。从本质上讲，异常活动的自我强化周期可能足以破坏神经回路的形成，其后果是晚年的癫痫发作。如果是这样，那么这种癫痫发作可以通过早期干预来打破异常活动的循环来治疗。这项研究计划将利用果蝇，黑腹果蝇，因为它非常适合基因分析，完整的基因组已经测序，因为它提供了一个简单的人类神经系统模型。我们打算使用一种特征突变的苍蝇，它表现出与人类非常相似的癫痫发作。我们之前的研究表明，这种被称为slamdance的突变，可以通过使用一种成熟的抗癫痫药物治疗早期胚胎而有效地“治愈”。目前的建议寻求使用一套相对较新的遗传工具，以便利用光来操纵早期发育中的神经系统的活动（光遗传学）。我们希望确定是否存在一个关键时期，在此期间异常活动足以破坏神经回路的形成，并使个体在以后的生活中容易癫痫发作。如果得到证实，这一结果可能会对人类遗传性癫痫的治疗方式产生重大影响。

The incidence of epilepsy in humans is a significant clinical problem which is exacerbated by the fact that up to one third of patients fail to respond to current drug treatment. The cause of epilepsy is both varied and in many cases unknown. However, what is known is that epilepsy results from incorrect function of nerve cells that make up the central nervous system. The human central nervous system is composed of many different types of nerve cells which must communicate with one another. These cells differ in the targets that they contact, the signalling chemicals (neurotransmitters) that they release, and the way in which they are able to fire electrical action potentials - the basis of signalling in the brain. Two recent studies highlight the possibility that some epilepsies may arise as a consequence of altered neural development due to the occurrence of abnormal patterns of activity. In essence self-reinforcing cycles of aberrant activity may be sufficient to destabilise the formation of neural circuits, the consequence of which is seizures in later life. If so, then such seizures may be treatable through early intervention to break the cycle of aberrant activity. This research proposal will exploit the fruitfly, Drosophila melanogaster, because it is very amenable to genetic analysis, the complete genome has been sequenced, and because it provides a simple model of the human nervous system. We intend to use a characterised mutant of the fly that exhibits seizures that are remarkably similar to those in humans. Our previous study shows that this mutant, termed slamdance, can be effectively 'cured' by treating the early embryo with an established antiepileptic drug. The present proposal seeks to use a relatively new set of genetic tools in order to use light to manipulate activity in an early developing nervous system (optogenetics). We hope to determine whether a critical period exists during which aberrant activity is sufficient to destabilise neural circuit formation and leave an individual prone to seizures in later life. If proven this outcome may have significant implications for the way heritable-forms of epilepsies are treated in humans.