Spatially realistic simulations of calcium dependent neurotransmitter release.

描述（由申请人提供）：本研究旨在建立一个全面的、空间逼真的动作电位触发的、钙依赖的神经递质从突触囊泡释放的计算模型。该模型将为动作电位进入神经末梢后的生理过程提供前所未有的时空洞察。模型开发将从现有的、空间上真实的单一活动区基线模型开始，该活动区是神经末梢的专门区域，包括神经递质释放机制。所有模拟都将使用MCell程序进行，该程序使用蒙特卡罗算法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、随机、聚类）和数量的变化；药物治疗（3,4-二氨基吡啶、蔷薇素）对钙通道动力学和动作电位形态的影响毒素处理阻断部分钙通道；以及流动缓冲液和/或静态和流动缓冲液的混合物对囊泡释放的影响。这些研究将导致基线模型的重大改进，从而为通过配对脉冲动作电位研究短期突触可塑性奠定基础。我们将首先确定产生配对脉冲易化实验观察值的机制，然后研究刺激间隔和药物治疗对配对脉冲易化的影响。显然，阐明成对脉冲易化的关键要素以及由此产生的突触可塑性对于更全面地了解人类神经功能的重要性不容低估。神经信号在人体内沿神经元的正确和忠实的传递对生存至关重要。突触构成了神经元和它们所支配的细胞之间的连接元件，许多衰弱的神经系统疾病都是由突触功能障碍引起的。因此，正确认识突触功能对神经系统疾病临床治疗的发展至关重要。提议的研究将直接有助于我们对突触功能的理解，因此与NIH的使命直接相关。

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.