星形膠質(zhì)細(xì)胞納米級(jí)形態(tài)在三聯(lián)突觸對(duì)Ca2+信號(hào)的控制

摘要星形膠質(zhì)細(xì)胞中的大部分Ca2+活性在空間上僅限于微區(qū)，并發(fā)生在形成復(fù)雜解剖網(wǎng)狀結(jié)構(gòu)的細(xì)小突起中，即所謂的海綿狀結(jié)構(gòu)域。越來(lái)越多的文獻(xiàn)表明，這些星形細(xì)胞Ca2+信號(hào)可以影響神經(jīng)元突觸的活動(dòng)，從而調(diào)節(jié)通過(guò)神經(jīng)元回路的信息流。局限于獲取所涉及的小空間尺度方面存在技術(shù)困難，關(guān)于星形膠質(zhì)細(xì)胞形態(tài)對(duì)Ca2+微區(qū)活性的作用仍然知之甚少。本研究使用計(jì)算機(jī)技術(shù)和基于最近的超分辨率顯微鏡數(shù)據(jù)的細(xì)小突起的理想化3D 幾何形狀來(lái)研究星形膠質(zhì)細(xì)胞納米級(jí)形態(tài)與局部Ca2+活性之間的關(guān)聯(lián)機(jī)制。模擬表明，星形細(xì)胞突起的納米形態(tài)強(qiáng)有力地塑造了Ca2+信號(hào)的時(shí)空特性并促進(jìn)了局部Ca2+活性。該模型預(yù)測(cè)，這種效應(yīng)在星形膠質(zhì)細(xì)胞腫脹時(shí)會(huì)減弱，這是腦部疾病的標(biāo)志，并在低滲透條件下通過(guò)實(shí)驗(yàn)證實(shí)了這一點(diǎn)。該模型還預(yù)測(cè)，在重復(fù)的神經(jīng)遞質(zhì)釋放事件后，腫脹會(huì)阻礙星形膠質(zhì)細(xì)胞的信號(hào)傳播。總而言之，三聯(lián)突觸中星形膠質(zhì)細(xì)胞的突起與突觸前和突觸后結(jié)構(gòu)密切接觸；本研究強(qiáng)調(diào)了星形膠質(zhì)細(xì)胞在納米尺度上的復(fù)雜形態(tài)及其在病理?xiàng)l件下的重塑對(duì)所謂的三聯(lián)突觸的神經(jīng)元-星形膠質(zhì)細(xì)胞通訊的影響。

關(guān)鍵詞鈣微區(qū)；計(jì)算神經(jīng)科學(xué)；細(xì)胞內(nèi)信號(hào)傳導(dǎo)；納米形態(tài)；反應(yīng)-擴(kuò)散模擬

中圖分類號(hào)R741；R741.02文獻(xiàn)標(biāo)識(shí)碼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 N?gerl2,3,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