Simulation of calcium signaling in fine astrocytic processes: Effect of spatial properties on spontaneous activity
Simulation of calcium signaling in fine astrocytic processes: Effect of spatial properties on spontaneous activity
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精细星形胶质细胞过程中钙信号传导的模拟：空间特性对自发活动的影响
DOI：
10.1101/567388
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发表时间：
2019
影响因子：
4.3
通讯作者：
Berry Hugues
中科院分区：
文献类型：
--
作者：
Denizot Audrey;Arizono Misa;Nägerl U. Valentin;Soula Hédi;Berry Hugues
星形胶质细胞是中枢神经系统的一种神经胶质细胞，是神经元信息处理的检测器和调节器。星形胶质细胞的兴奋性存在于一系列时间和空间尺度上的胞浆游离钙浓度的瞬时变化中，从亚微域到传播到整个细胞的波。尽管有广泛的实验方法，但这些信号是如何传递到星形胶质细胞并整合到星形胶质细胞中的尚不清楚。主要分子因子的定位和系统的几何结构，包括钙通道IP3R的空间组织，被认为是必不可少的。然而，由于大多数钙信号出现在星形细胞的分支中，而这些分支太细，无法用传统的光学显微镜来分辨，因此大多数空间数据是未知的，计算建模仍然是研究这一问题的唯一方法。在这里，我们提出了一个IP3R介导的钙信号模型，用于研究如此小的亚细胞体积的动力学。为了解释预期的随机性和低拷贝数，我们的模型在空间上是显式的，并且是基于粒子的。广泛的模拟表明，在模型中自发的钙信号是通过兴奋性和随机性之间的相互作用而产生的。该模型再现了钙信号的主要形式，并表明其频率关键取决于IP3R通道的空间组织。重要的是，我们证明了两个表达完全相同的钙通道的过程可以显示不同类型的钙信号，这取决于通道的空间组织。我们的模型具有真实的过程体积和钙浓度，成功地重现了我们用共聚焦显微镜在钙微区测量的自发钙信号。据我们所知，这个模型是第一个适合研究精细星形细胞突起中的钙动力学并提出可能的机制来解释其变异性的模型。
Astrocytes, a glial cell type of the central nervous system, have emerged as detectors and regulators of neuronal information processing. Astrocyte excitability resides in transient variations of free cytosolic calcium concentration over a range of temporal and spatial scales, from sub-microdomains to waves propagating throughout the cell. Despite extensive experimental approaches, it is not clear how these signals are transmitted to and integrated within an astrocyte. The localization of the main molecular actors and the geometry of the system, including calcium channels IP3R spatial organization, are deemed essential. However, as most calcium signals occur in astrocytic ramifications that are too fine to be resolved by conventional light microscopy, most of those spatial data are unknown and computational modeling remains the only methodology to study this issue. Here, we propose an IP3R-mediated calcium signaling model for dynamics in such small sub-cellular volumes. To account for the expected stochasticity and low copy numbers, our model is both spatially explicit and particle-based. Extensive simulations show that spontaneous calcium signals arise in the model via the interplay between excitability and stochasticity. The model reproduces the main forms of calcium signals and indicates that their frequency crucially depends on the spatial organization of the IP3R channels. Importantly, we show that two processes expressing exactly the same calcium channels can display different types of calcium signals depending on channels spatial organization. Our model with realistic process volume and calcium concentrations successfully reproduces spontaneous calcium signals that we measured in calcium micro-domains with confocal microscopy. To our knowledge, this model is the first model suited to investigate calcium dynamics in fine astrocytic processes and to propose plausible mechanisms responsible for their variability.
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