星形胶质细胞纳米级形态在三联突触对Ca2+信号的控制

摘要星形胶质细胞中的大部分Ca2+活性在空间上仅限于微区，并发生在形成复杂解剖网状结构的细小突起中，即所谓的海绵状结构域。越来越多的文献表明，这些星形细胞Ca2+信号可以影响神经元突触的活动，从而调节通过神经元回路的信息流。局限于获取所涉及的小空间尺度方面存在技术困难，关于星形胶质细胞形态对Ca2+微区活性的作用仍然知之甚少。本研究使用计算机技术和基于最近的超分辨率显微镜数据的细小突起的理想化3D 几何形状来研究星形胶质细胞纳米级形态与局部Ca2+活性之间的关联机制。模拟表明，星形细胞突起的纳米形态强有力地塑造了Ca2+信号的时空特性并促进了局部Ca2+活性。该模型预测，这种效应在星形胶质细胞肿胀时会减弱，这是脑部疾病的标志，并在低渗透条件下通过实验证实了这一点。该模型还预测，在重复的神经递质释放事件后，肿胀会阻碍星形胶质细胞的信号传播。总而言之，三联突触中星形胶质细胞的突起与突触前和突触后结构密切接触；本研究强调了星形胶质细胞在纳米尺度上的复杂形态及其在病理条件下的重塑对所谓的三联突触的神经元-星形胶质细胞通讯的影响。

关键词钙微区；计算神经科学；细胞内信号传导；纳米形态；反应-扩散模拟

中图分类号R741；R741.02文献标识码ADOI10.16780/j.cnki.sjssgncj.2022.10.020

Control of Ca2+signals by astrocyte nanoscale morphology at tripartite synapses

Audrey Denizot1,Misa Arizono2,3,4,U Valentin Nägerl2,3,Hugues Berry5,6,Erik De Schutter1

1.Computational Neuroscience Unit,Okinawa Institute of Science and Technology,Onna-Son,Japan.
2.Interdisciplinary Institute for Neuroscience,Université de Bordeaux,Bordeaux,France.
3.Interdisciplinary Institute for Neuroscience,CNRS UMR 5297,Bordeaux,France.
4.Department of Pharmacology,Kyoto University Graduate School of Medicine,Kyoto,Japan.
5.LIRIS,UMR5205 CNRS,Univ Lyon,Villeurbanne,France.
6.INRIA,Villeurbanne,France.

摘自Glia. 2022 Dec,70(12):2378-2391.doi:10.1002/glia.24258.Epub 2022 Sep 13.

AbstractMuch of the Ca2+activity in astrocytes is spatially restricted to microdomains and occurs in fine processes that form a complex anatomical meshwork, the so-called spongiform domain.A growing body of literature indicates that those astrocytic Ca2+signals can influence the activity of neuronal synapses and thus tune the flow of information through neuronal circuits. Because of technical difficulties in accessing the small spatial scale involved, the role of astrocyte morphology on Ca2+microdomain activity remains poorly understood. Here, we use computational tools and idealized 3D geometries of fine processes based on recent super-resolution microscopy data to investigate the mechanistic link between astrocytic nanoscale morphology and local Ca2+activity. Simulations demonstrate that the nano-morphology of astrocytic processes powerfully shapes the spatio-temporal properties of Ca2+signals and promotes local Ca2+activity. The model predicts that this effect is attenuated upon astrocytic swelling, hallmark of brain diseases, which we confirm experimentally in hypo-osmotic conditions. Upon repeated neurotransmitter release events,the model predicts that swelling hinders astrocytic signal propagation.Overall,this study highlights the influence of the complex morphology of astrocytes at the nanoscale and its remodeling in pathological conditions on neuron-astrocyte communication at so-called tripartite synapses, where astrocytic processes come into close contact with pre-and postsynaptic structures.

Key wordscalcium microdomains; computational neuroscience; intracellular signaling; nano-morphology; reaction-diffusion simulations