Is seizure a consequence of altered neural development?

癫痫发作是神经发育改变的结果吗？

• 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

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目前的药物治疗无效，这一事实加剧了这一问题。癫痫的原因多种多样，在许多情况下是未知的。然而，已知的是癫痫是由组成中枢神经系统的神经细胞的不正确功能引起的。人类的中枢神经系统是由许多不同类型的神经细胞组成的，这些神经细胞必须相互通信。这些细胞在它们接触的目标、它们释放的信号化学物质(神经递质)以及它们能够发射动作电位的方式--大脑中信号的基础--方面有所不同。最近的两项研究强调了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。本质上，异常活动的自我强化循环可能足以破坏神经回路的形成，其结果是在以后的生活中癫痫发作。如果是这样，那么这种癫痫发作可能可以通过早期干预来打破异常活动的循环。这项研究计划将利用果蝇，因为它非常容易进行遗传分析，完整的基因组已经测序，而且因为它提供了一个简单的人类神经系统模型。我们打算使用苍蝇的一种特征突变，这种突变表现出与人类非常相似的癫痫发作。我们之前的研究表明，这种名为Slamance的突变可以通过用一种已有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性，并使个人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治疗遗传性癫痫的方式产生重大影响。

项目成果

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

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

Regulation of membrane excitability: a convergence on voltage-gated sodium conductance.

• DOI: 10.1007/s12035-014-8674-0
• 发表时间: 2015-02
• 期刊: MOLECULAR NEUROBIOLOGY
• 影响因子: 5.1
• 作者: Lin, Wei-Hsiang;Baines, Richard A.
• 通讯作者: Baines, Richard A.

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

• DOI: 10.1038/srep05799
• 发表时间: 2014-07-23
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Marley R;Giachello CN;Scrutton NS;Baines RA;Jones AR
• 通讯作者: Jones AR

Calcium Imaging of Neuronal Activity in Drosophila Can Identify Anticonvulsive Compounds.

• DOI: 10.1371/journal.pone.0148461
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Streit AK;Fan YN;Masullo L;Baines RA
• 通讯作者: Baines RA