Laghaei Rozita, Meriney Stephen D
Biomedical Applications Group, Pittsburgh Supercomputing Center, Carnegie Mellon University, Pittsburgh, PA, United States.
Department of Neuroscience, Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States.
Front Synaptic Neurosci. 2022 Jun 13;14:917285. doi: 10.3389/fnsyn.2022.917285. eCollection 2022.
The general mechanism of calcium-triggered chemical transmitter release from neuronal synapses has been intensely studied, is well-known, and highly conserved between species and synapses across the nervous system. However, the structural and functional details within each transmitter release site (or active zone) are difficult to study in living tissue using current experimental approaches owing to the small spatial compartment within the synapse where exocytosis occurs with a very rapid time course. Therefore, computer simulations offer the opportunity to explore these microphysiological environments of the synapse at nanometer spatial scales and on a sub-microsecond timescale. Because biological reactions and physiological processes at synapses occur under conditions where stochastic behavior is dominant, simulation approaches must be driven by such stochastic processes. MCell provides a powerful simulation approach that employs particle-based stochastic simulation tools to study presynaptic processes in realistic and complex (3D) geometries using optimized Monte Carlo algorithms to track finite numbers of molecules as they diffuse and interact in a complex cellular space with other molecules in solution and on surfaces (representing membranes, channels and binding sites). In this review we discuss MCell-based spatially realistic models of the mammalian and frog neuromuscular active zones that were developed to study presynaptic mechanisms that control transmitter release. In particular, these models focus on the role of presynaptic voltage-gated calcium channels, calcium sensors that control the probability of synaptic vesicle fusion, and the effects of action potential waveform shape on presynaptic calcium entry. With the development of these models, they can now be used in the future to predict disease-induced changes to the active zone, and the effects of candidate therapeutic approaches.
钙离子触发神经元突触化学递质释放的一般机制已得到深入研究，广为人知，且在整个神经系统的不同物种和突触之间高度保守。然而，由于突触内胞吐作用发生的空间隔很小且时间进程非常快，使用当前实验方法在活体组织中研究每个递质释放位点（或活性区）的结构和功能细节很困难。因此，计算机模拟提供了在纳米空间尺度和亚微秒时间尺度上探索突触这些微生理环境的机会。由于突触处的生物反应和生理过程是在随机行为占主导的条件下发生的，模拟方法必须由这种随机过程驱动。MCell提供了一种强大的模拟方法，它采用基于粒子的随机模拟工具，使用优化的蒙特卡罗算法，在现实且复杂的（3D）几何结构中研究突触前过程，以追踪有限数量的分子在复杂细胞空间中与溶液中和表面上（代表膜、通道和结合位点）的其他分子扩散和相互作用的情况。在这篇综述中，我们讨论了基于MCell的哺乳动物和青蛙神经肌肉活性区的空间真实模型，这些模型是为研究控制递质释放的突触前机制而开发的。特别是，这些模型关注突触前电压门控钙通道的作用、控制突触小泡融合概率的钙传感器，以及动作电位波形形状对突触前钙内流的影响。随着这些模型的发展，它们现在可在未来用于预测疾病引起的活性区变化以及候选治疗方法的效果。
