Virtual presynaptic nerve terminal: a computational tool for studying synaptic transmitter release in health and disease

突触传递构成了大脑中神经元交流的基础。当动作电位侵入突触前结构(称为突触或终末)时，它会使突触前膜去极化，从而激活钙通道，导致钙离子流入神经末梢。这种钙离子内流触发了充满神经递质的突触小泡(SV)的快速融合。神经递质迅速扩散到突触后神经元，在那里它们与特定的受体结合，并激发进一步的电和/或化学信号。整个过程的效率由钙离子信号和SV融合的精确定时保证。尽管递质释放的一般分子机制已经建立，但不同突触的囊泡释放过程的精确调控仍未完全解决，在单个突触水平上研究这一调控的主要困难在于大脑中大多数突触前突触的数量很小，因此实验技术面临着严重的局限性。因此，数据受限的突触前结构的现实计算模型是必要的工具，使人们能够补充实验方法的局限性，并定量预测神经末梢在生理神经元活动期间的行为。目前，由于缺乏一个统一的突触前终端建模框架，使得数学/计算专业知识有限的研究实验室可以为他们的实验数据实现一个真实的模型，因此计算模型的使用受到了阻碍。在这个项目中，我们建议开发这样一个突触前终端的统一计算框架模型，这将允许神经科学界探索不能通过实验直接确定的钙离子驱动的递质释放的机制。我们将使用功能强大的软件平台虚拟单元(http://vcell.org/))来实现和模拟我们的三维计算模型。该模型将包括已知在塑造递质释放动力学中重要的关键功能突触前元件。中枢神经系统中不同类型的突触具有不同的结构和分子组织，这导致它们具有不同的功能特性。在项目期间，我们将应用我们实施的框架，与英国和国外的一组世界领先的实验实验室(最终用户)合作，调查一些科学问题。特别是，我们将调整我们的计算框架来模拟几种典型的突触类型，然后系统地研究单个突触前元素如何在健康和疾病中调节突触递质的释放。每个项目中的模型都将使用来自最终用户实验室的现有和新的实验数据进行约束和调整。我们预计我们的结果将为调节递质释放提供新的量化见解，并将对促进最终用户实验室的实验工作产生立竿见影的影响。我们还将应用开发的模型，与伦敦大学学院皇后广场神经病学研究所的临床和实验同事合作，在电子计算机上研究突触前运动功能障碍的机制。特别是，我们将重点介绍突触前通道病--由突触前离子通道突变引起的发作性神经疾病(包括某些形式的偏头痛、癫痫和共济失调)。在项目结束时，我们经过验证的计算框架将发布给研究社区的公共领域，同时还将发布一份用户友好的手册，解释如何运行、链接和修改各个模型块以解决特定的研究问题。这将为其他实验实验室提供强大的资源，特别是那些缺乏建模专业知识的实验室。

Synaptic transmission forms the basis of neuronal communication in the brain. When an action potential invades a presynaptic structure (known as a bouton or terminal) it depolarises the presynaptic membrane, which activates Ca2+ channels leading to an influx of Ca2+ ions into the nerve terminal. This Ca2+ influx triggers fast fusion of synaptic vesicles (SV) filled with neurotransmitters. Neurotransmitters quickly diffuse towards the postsynaptic neuron, where they bind to specific receptors and evoke further electrical and/or chemical signalling. The efficiency of the whole process is ensured by the precise timing of the Ca2+ signal and SV fusing. Although the general molecular mechanism of transmitter release is well established, the precise regulation of vesicular release process at different synapses remains incompletely resolved.The main difficulty studying this regulation at the level of single synapses is that the majority of presynaptic boutons in the brain are very small, and as a result the experimental techniques are confronted with serious limitations. Data-constrained realistic computational models of presynaptic structures are therefore essential tools that allow one to complement the limitations of experimental approaches and to quantitatively predict the behaviour of nerve terminals during physiological neuronal activity. At present, the use of computational models is impeded because of the absence of a unified modelling framework of the presynaptic terminal that would allow research laboratories with limited mathematical/computational expertise to implement a realistic model for their experimental data.In this project we propose to develop such a unified computational framework model of a presynaptic terminal, which will allow the neuroscience community to explore mechanisms of Ca2+-driven transmitter release that cannot be directly determined experimentally. We will use the powerful software platform Virtual Cell (http://vcell.org/) for implementing and simulating our three-dimensional computational model. The model will include the key functional presynaptic elements that are known to be important in shaping transmitter release dynamics.Different types of synapses in the central nervous system have diverse structural and molecular organisation that leads to their distinct functional properties. During the project we will apply our implemented framework to investigate a number of scientific questions in collaboration with a group of world-leading experimental laboratories (end-users) both in the UK and abroad. In particular, we will adapt our computational framework to model several canonical synapse-types and then will systematically study how individual presynaptic elements regulate synaptic transmitter release both in health and disease. Models in each project will be constrained and tuned using existing and novel experimental data from the end-user laboratories.We anticipate that our results will provide novel quantitative insights into the regulation of transmitter release and will have an immediate impact in facilitating the experimental work in the end-user laboratories. We will also apply the developed models to investigate in silico the mechanisms of presynaptic bouton dysfunctions in collaboration with clinical and experimental colleagues in UCL Queen Square Institute of Neurology. In particular, we will focus on presynaptic channelopathies - episodic neurological disorders caused by mutations in presynaptic ion channels (including some forms of migraine, epilepsy and ataxias). At the end of the project, our validated computational framework will be released to the public domain for the research community together with a user-friendly manual explaining how individual modelling blocks can be run, linked, and modified to address a particular research question. This will provide a powerful resource for other experimental laboratories, particularly the ones that lack modelling expertise.