Unit of Synapse and Circuit Dynamics, CNRS UMR 3571, Institut Pasteur, Paris, France.
ED3C, Sorbonne University, Paris, France.
Sci Rep. 2021 Mar 8;11(1):5377. doi: 10.1038/s41598-021-84340-4.
Synaptic transmission between neurons is governed by a cascade of stochastic calcium ion reaction-diffusion events within nerve terminals leading to vesicular release of neurotransmitter. Since experimental measurements of such systems are challenging due to their nanometer and sub-millisecond scale, numerical simulations remain the principal tool for studying calcium-dependent neurotransmitter release driven by electrical impulses, despite the limitations of time-consuming calculations. In this paper, we develop an analytical solution to rapidly explore dynamical stochastic reaction-diffusion problems based on first-passage times. This is the first analytical model that accounts simultaneously for relevant statistical features of calcium ion diffusion, buffering, and its binding/unbinding reaction with a calcium sensor for synaptic vesicle fusion. In particular, unbinding kinetics are shown to have a major impact on submillisecond sensor occupancy probability and therefore cannot be neglected. Using Monte Carlo simulations we validated our analytical solution for instantaneous calcium influx and that through voltage-gated calcium channels. We present a fast and rigorous analytical tool that permits a systematic exploration of the influence of various biophysical parameters on molecular interactions within cells, and which can serve as a building block for more general cell signaling simulators.
神经元之间的突触传递受神经末梢内一连串随机钙离子反应-扩散事件的控制，导致神经递质囊泡释放。由于这些系统的实验测量具有纳米和亚毫秒级的尺度，因此数值模拟仍然是研究电脉冲驱动的钙依赖性神经递质释放的主要工具，尽管计算耗时较长。在本文中，我们基于首次通过时间开发了一种快速探索动态随机反应-扩散问题的解析解。这是第一个同时考虑钙离子扩散、缓冲及其与钙传感器结合/解吸反应的相关统计特征的解析模型，用于突触囊泡融合。特别是，解吸动力学对亚毫秒级传感器占有率概率有重大影响，因此不能忽略。我们使用蒙特卡罗模拟验证了我们对瞬时钙离子内流和电压门控钙离子通道的解析解。我们提出了一种快速而严格的解析工具，可系统地研究各种生物物理参数对细胞内分子相互作用的影响，可作为更通用的细胞信号模拟器的构建块。
