Spatially realistic simulations of calcium dependent neurotransmitter release.

描述(申请人提供)：拟议的研究旨在开发一个全面的和空间现实的计算模型的动作电位触发，钙依赖的神经递质释放从突触小泡。这个模型将为动作电位侵入神经末梢后的生理过程提供前所未有的时空洞察力。模型开发将从单个活动区的现有的、空间上真实的基线模型开始，单个活动区是神经末梢内的专门区域，包括神经递质释放机制。所有的模拟都将使用MCell程序进行，该程序使用蒙特卡罗算法来模拟钙离子和缓冲分子的分子扩散，钙离子与受体的结合，以及任意复杂细胞空间内的钙通道门控。在实验输入的指导下，我们将研究扰动及其组合对现有基线模型的影响，例如钙通道的位置、排列(均匀的、随机的、簇状的)和数量的变化；药物处理(3，4-二氨基吡啶、罗可维丁)对钙通道动力学和动作电位形状的影响；毒素处理阻断部分钙通道；以及移动缓冲液和/或静态和移动缓冲液的混合对囊泡释放的影响。这些研究将导致基线模型的显著改进，从而为通过成对脉冲动作电位研究突触的短期可塑性奠定基础。我们将首先确定产生配对脉冲促进作用的实验观察值的机制，然后研究相互刺激间隔和药物治疗对配对脉冲促进作用的影响。显然，阐明成对脉冲易化的关键因素，从而阐明突触可塑性对于更全面地了解人类神经功能的重要性不可低估。神经信号沿着人体神经元的正确和忠实的传输对生存至关重要。突触构成了神经元和它们所支配的细胞之间的连接元素，许多衰弱的神经疾病是由突触功能障碍引起的。因此，对突触功能的正确理解对于发展神经系统疾病的临床治疗是至关重要的。这项拟议的研究将直接有助于我们对突触功能的理解，因此与NIH的任务直接相关。

DESCRIPTION (provided by applicant): The proposed research aims to develop a comprehensive and spatially realistic computational model of action potential triggered, calcium dependent neurotransmitter release from synaptic vesicles. This model will provide unprecedented spatio-temporal insights into the physiological processes following the invasion of an action potential into a nerve terminal. Model development will proceed from an existing, spatially realistic baseline model of a single active zone, the specialized region within a nerve terminal that includes neurotransmitter release machinery. All simulations will be carried out with the program MCell which uses Monte Carlo algorithms to simulate molecular diffusion of calcium ions and buffer molecules, binding of calcium ions to receptors, and calcium channel gating inside arbitrary complex cellular spaces. Guided by experimental input, we will investigate the effect of perturbations and combinations thereof to the existing baseline model such as changes in the location, arrangement (homogeneous, randomized, clustered), and number of calcium channels; drug treatments (3,4-diaminopyridine, roscovitin) influencing the calcium channel kinetics and action potential shape; toxin treatments blocking fractions of calcium channels; and the effect of mobile buffer and/or mixtures of static and mobile buffer on vesicle release. These studies will lead to significant improvements of the baseline model and, thereby, set the stage for an investigation of short term synaptic plasticity via paired pulse action potentials. We will first identify mechanisms that give rise to the experimentally observed values for paired pulse facilitation and then investigate the effect of changes in the interstimulus interval and drug treatments on paired pulse facilitation. Clearly, the importance of elucidating the key elements of paired pulse facilitation and thereby synaptic plasticity for a more comprehensive understanding of human neural function can not be underestimated. The proper and faithful transmission of nerve signals along neurons in the human body is crucial for survival. Synapses constitute the connecting elements between neurons and cells they innervate and many debilitating neurological disorders are caused by synaptic dys-function. Hence, a proper understanding of synaptic function is crucial for the development of clinical treatments for neurological diseases. The proposed research will directly contribute to our understanding of synaptic function and is therefore directly relevant to the mission of the NIH.