Is seizure a consequence of altered neural development?

癫痫发作是神经发育改变的结果吗？

基本信息

批准号：
MR/J009180/1
负责人：
Richard Baines
金额：
$ 51.52万
依托单位：
University of Manchester
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FJ009180%2F1
关键词：
seizure consequence altered neural development

项目摘要

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.

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当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，而且在许多情况下是未知的。然而，众所周知，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。人类中枢神经系统由许多不同类型的神经细胞组成，这些细胞必须相互通信。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（大脑信号传导的基础）的方式。最近的两项研究强调了一些癫痫症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循环可能足以破坏神经回路的形成，其后果是晚年癫痫发作。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。该研究计划将利用果蝇（Drosophila melanogaster），因为它非常适合遗传分析，完整的基因组已被测序，并且因为它提供了人类神经系统的简单模型。我们打算使用果蝇的一种特征突变体，其癫痫发作与人类的癫痫发作非常相似。我们之前的研究表明，这种被称为 slamdance 的突变体可以通过用现有的抗癫痫药物治疗早期胚胎来有效地“治愈”。目前的提案旨在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形成的稳定并使个体在以后的生活中容易癫痫发作。如果这一结果得到证实，可能会对人类遗传性癫痫的治疗方式产生重大影响。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Neurobiology: Setting the Set Point for Neural Homeostasis

神经生物学：设定神经稳态的设定点

DOI：
10.1016/j.cub.2015.10.021
发表时间：
2015
期刊：
Current Biology
影响因子：
9.2
作者：
Truszkowski T
通讯作者：
Truszkowski T

Restoration of mutant bestrophin-1 expression, localisation and function in a polarised epithelial cell model.

DOI：
10.1242/dmm.024216
发表时间：
2016-11-01
期刊：
Disease models & mechanisms
影响因子：
4.3
作者：
Uggenti C;Briant K;Streit AK;Thomson S;Koay YH;Baines RA;Swanton E;Manson FD
通讯作者：
Manson FD

Cryptochrome-dependent magnetic field effect on seizure response in Drosophila larvae.