Astrocyte calcium waves: What they are and what they do

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<ul><li><p>Astrocyte Calcium Waves: What They Areand What They DoELIANA SCEMES1* AND CHRISTIAN GIAUME2*1Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York2College de France, Paris, France</p><p>KEY WORDSglial cells; gliotransmitters; ATP; gap junctions; connexins</p><p>ABSTRACTSeveral lines of evidence indicate that the elaborated cal-cium signals and the occurrence of calcium waves in astro-cytes provide these cells with a specic form of excitability.The identication of the cellular and molecular steps in-volved in the triggering and transmission of Ca21 wavesbetween astrocytes resulted in the identication of two path-ways mediating this form of intercellular communication.One of them involves the direct communication between thecytosols of two adjoining cells through gap junction channels,while the other depends upon the release of gliotrans-mitters that activates membrane receptors on neighboringcells. In this review we summarize evidence in favor of thesetwo mechanisms of Ca21 wave transmission and we discussthat they may not be mutually exclusive, but are likely towork in conjunction to coordinate the activity of a group ofcells. To address a key question regarding the functionalconsequences following the passage of a Ca21 wave, we list,in this review, some of the potential intracellular targets ofthese Ca21 transients in astrocytes, and discuss the func-tional consequences of the activation of these targets for theinteractions that astrocytes maintain with themselves andwith other cellular partners, including those at the glial/vas-culature interface and at perisynaptic sites where astrocyticprocesses tightly interact with neurons. VVC 2006 Wiley-Liss, Inc.</p><p>CALCIUM SIGNALS AS A SPECIFIC MODE OFEXCITABILITYAND TRANSMISSION IN</p><p>ASTROCYTES: HISTORICAL PERSPECTIVE</p><p>The ndings that astrocytes express a variety of ionchannels and membrane receptors, which enable them torespond on a millisecond time scale to neuronal activitywith changes in membrane potential and/or increases inintracellular Ca21 levels (Barres et al., 1990; MacVicarand Tse, 1988; Marrero et al., 1989; McCarthy and Salm,1991; Salm and MacCarthy, 1990; Usowic et al., 1989) wasthe rst step in the glia eld leading to the hypothesisthat these cells could play a role in CNS information pro-cessing. It was based on these early reports that Cornell-Bell et al. (1990) and Charles et al. (1991) rst reportedthat astrocytes were not only able to respond to externalstimulation with increases in intracellular calcium eleva-tions but, most importantly, they were be able to transmitthese calcium signals to adjacent non-stimulated astro-cytes, as intercellular Ca21 waves (ICWs). The presence of</p><p>such phenomenon of propagating waves of calcium lead tothe proposition that networks of astrocytes constitute anextraneuronal pathway for rapid long-distance signaltransmission within the CNS. Moreover, these authors(Cornell-Bell et al., 1990) proposed that if Ca21 activityin the network of astrocytes constituted another form ofintercellular communication, such signaling should havea physiological relevance inuencing neuronal activity,and thus being bi-directional. Work by several independ-ent groups showed that indeed there is a reciprocal com-munication between neurons and astrocytes. Hippocam-pal neuronal activity was shown to trigger calcium wavesin astrocyte networks (Dani et al., 1992) and astrocyte cal-cium waves were shown to modulate neuronal activity(Dani et al., 1992; Kang et al., 1998; Nedergaard, 1994;Parpura et al., 1994; Parri et al., 2001). The mode bywhich astrocyte calcium signals affect synaptic transmis-sion was then shown to be dependent on regulated exocy-tosis of stored glutamate, ATP, and D-serine (Bezzi et al.,2004; Coco et al., 2003; Mothet et al., 2005; Parpura et al.,1994; Pascual et al., 2005). Consequently, the pre- andpost-synaptic components of neuronal transmission gaineda new partner, the perisynaptic glia, forming togetherwhat was initially termed the tripartite-synapse (Araqueet al., 1998a,b). Because these studies indicated that theelectrically silent astrocytes were active participants ofCNS information processing, it became plausible to con-sider that astrocytes are nevertheless excitable cells,with Ca21 uctuations being the signal by which they re-spond, integrate, and convey information.Although with the limitation of the studies performed</p><p>in culture, pioneering experiments (Cornell-Bell et al.,1990) generated insightful ideas that, followed by experi-mental evidence, brought a new perspective to the role ofglial cells in CNS function. Of note is their report on thespatial and temporal pattern changes that occur after100 lM glutamate application. Following the initial Ca21</p><p>elevation induced by receptor activation, oscillatory Ca21</p><p>Grant sponsor: National Institutes of Health; Grant number: RO1-NS41023 toES; Grant sponsor: INSERM.</p><p>*Correspondence to: Eliana Scemes, Department of Neuroscience, Kennedy Center,Room No. 203, Albert Einstein College of Medicine, 1410 Pelham Parkway, Bronx, NY10461, USA. E-mail:; Christian Giaume, INSERM-U587, Col-lege de France, 11 Place Marcelin Berthelot, Paris 75005, France.E-mail: christian.giaume@college-de-france</p><p>Received 21 March 2006; Accepted 23 May 2006</p><p>DOI 10.1002/glia.20374</p><p>Published online 26 September 2006 in Wiley InterScience (</p><p>GLIA 54:716725 (2006)</p><p>VVC 2006 Wiley-Liss, Inc.</p></li><li><p>uctuations preceded the intercellular spread of Ca21.This oscillatory behavior persisted for long periods oftime (530 min) with variable frequencies (10110 mHz).A direct correlation between glutamate concentration andfrequency of oscillations was observed: at low concentra-tions (below 1 lM) intracellular Ca21 transients wereasynchronous and localized, whereas at higher concentra-tions (10100 lM) intercellular Ca21 waves propagatedover long distances. This indicated that small uctuationsin intracellular Ca21 could be integrated to generate aglobal intracellular response, which could be transmittedthroughout the astrocytic network. Recent development ofin vivo imaging, using two-photon microscopy, has pro-vided evidence for coordinated astrocyte Ca21 activity inthe neocortex of rats (Hirase et al., 2004).Although many of the questions that were raised when</p><p>Ca21 waves were rst described have been answered,many are still debated and others have been generated.This review is not intended to revisit the concept and evi-dence that culminated in this new line of investigation, forwhich several recent reviews are available (Charles andGiaume, 2002; Nedergaard et al., 2003; Scemes, 2000).Instead, this review will focus on the characteristicsand consequences of intercellular Ca21 signaling inastrocytes and their relevance to CNS function. Because</p><p>gliotransmitter released from astrocytes (the mechan-isms by which this release is accomplished are discussedin the other reviews), besides affecting synaptic transmis-sion and brain microcirculation, is also likely to serve asan autocrine signal, we will consider in this review someimportant aspects of this feedback mechanism for thetransmission of Ca21 waves between astrocytes.</p><p>CA21WAVES IN VITRO AND IN VIVO: WHENAND WHERE DO THEY OCCUR?</p><p>A calcium wave is dened as a localized increase in cy-tosolic Ca21 that is followed by a succession of similarevents in a wave-like fashion. These Ca21 waves can berestricted to one cell (intracellular) or transmitted to neigh-boring cells (intercellular) (Fig. 1A).The basic steps that lead to intracellular Ca21 waves in</p><p>astrocytes usually involve the activation of G-protein-coupled receptors, activation of phospholipase C, and theproduction of IP3, which following IP3R activation leads toCa21 release from the endoplasmic reticulum (ER) (Golo-vina and Blaustein, 2000; Scemes, 2000; Sheppard et al.,1997). These intracellular Ca21 signals are spatially andtemporally complex events involving the recruitment of</p><p>Fig. 1. Intercellular Ca21 waves and their intracellular targets. (A)The transmission of intercellular Ca21 signals between astrocytes is illu-strated in the sequential images obtained from Fluo-3-AM loaded spinalcord astrocytes. Mechanical stimulation (arrow) of a single astrocyte inculture induces intracellular Ca21 elevation (displayed as an increase inuorescence intensity) in the stimulated cells, which is then followed byCa21 increases in neighboring astrocytes. Images were acquired with anOrca-ER CCD camara attached to Nikon TE2000 inverted microscopeequipped with a 310 objective, using Metauor software. Bar: 50 lm.(B) The diagram illustrates the major intracellular targets of cytosolicCa21 uctuations in astrocytes. Elevation of intracellular Ca21 levels is</p><p>shown to affect (arrows) several plasma membrane proteins (symbolsrefer from left to right to metabotropic receptors, K1 (Ca21) channels,Na1/Ca21 exchanger, and Ca21-ATPase), as well as intracellular ones.The inositol-trisphosphate receptors (IP3R) are located at the endoplas-mic reticulum (ER) where Ca21 exert a cooperative action. Rises in[Ca21]i also target several cytoskeleton elements (cytosk), enzymes (E),and vesicles involved on the release of gliotransmitters. Finally, Ca21</p><p>and the Ca21 liberating second messenger IP3 permeate gap junctionchannels and then act on similar intracellular targets in neighboringcoupled cells.</p><p>717INTERCELLULAR CALCIUM WAVES</p><p>GLIA DOI 10.1002/glia</p></li><li><p>elementary Ca21 release sites (Ca21 puffs: Parker andYao, 1994), which then propagate throughout the cell byan amplication mechanism. This amplication involvesfour components, two of which depend on positive andtwo on negative feedback mechanisms provided byreleased Ca21. These feedback mechanisms are: (a) theactivation of nearby IP3Rs due to the co-agonistic action ofCa21 on these receptors (Bezprovanny and Ehrlich, 1995;Finch et al., 1991; Yao et al., 1995), (b) the additional gen-eration of IP3 through the Ca</p><p>21-dependent activation ofPLC (Berridge, 1993; Venance et al., 1997), (c) the buffer-ing power of mitochondria, attenuating the excess Ca21</p><p>levels at IP3R microdomains that otherwise would reducethe sensitivity of these receptors to IP3 (Boitier et al.,1999; Simpson et al., 1998), and (d) the presence of endog-enous low afnity Ca21 buffers (calcium binding proteins)that limit the diffusion of Ca21 ions within single astro-cytes (Wang et al., 1997).Once triggered, intracellular Ca21 waves can be trans-</p><p>mitted to neighboring cells as ICWs. Regardless of themechanism by which these waves may travel (see detailsthat follow), the mechanism that triggers Ca21 transientsin adjacent astrocytes relies on IP3 production and subse-quent release of Ca21 from the ER, as summarized abovefor intracellular Ca21 waves. Therefore, the extent towhich these intercellular Ca21 waves can travel are gov-erned by the effective diffusion properties of the Ca21</p><p>mobilizing signaling molecules within and between cells.ICW spread between astrocytes derived from cell cul-</p><p>ture, brain slice, and whole retina preparations has beenobserved following pharmacological, electrical, and me-chanical stimulation (for review see Boitier et al., 1999;Charles, 1998; Charles and Giaume, 2002; Giaume andVenance, 1998; Newman, 2004; Scemes, 2000; Simpsonet al., 1998). Although there are some differences regard-ing the distance and shape of ICWs generated by eachtype of stimulation, once they are initiated, the velocitiesby which they travel between astrocytes are fairly simi-lar, independent of the mode of stimulation and type ofpreparation. For instance, pharmacological, mechanical,and electrical stimulation of rat retina induced ICWs thattraveled at a mean speed of 23 lm/sec (Newman andZahs, 1997); pharmacologically and mechanically-inducedintercellular Ca21 waves between cultured astrocytestravel at a mean velocity of 18 lm/sec (for reviews seeGiaume and Venance, 1998; Scemes, 2000), and in theelectrically stimulated brain slice preparations, the meanCa21 wave velocity is 15 lm/sec (Dani et al., 1992; Hasset al., 2005; Schipke et al., 2002). In contrast to the veloc-ity of Ca21 wave spread, the extent to which ICW travelsis highly variable, even when comparing a single type ofstimulation among different types of preparations. Forexample, differences in the number of cells participatingin ICW transmission following mechanical stimulationwere observed among cultures of astrocytes prepared fromdistinct brain regions; ICWs spread to twice as many cor-tical and hippocampal astrocytes as between astrocytesfrom the hypothalamus and brain stem (Blomstrandet al., 1999). Similarly, mechanically induced Ca21 wavesbetween cultured telencephalic astrocytes spread radially</p><p>to an area of 450 lm2 comprising about 400 cells whilewaves traveling between cultured diencephalic astrocytesspread unevenly to an area of 130 lm2 recruiting about100 cells (Peters et al., 2005).Regardless of the notorious differences between culture</p><p>and in situ conditions (e.g., morphology of astrocytes, sizeof the extracellular space), some generalizations can bemade with respect to the properties of ICWs. Based on thestudies reported above, it is likely that some of the charac-teristics of Ca21 waves are governed by the intrinsic prop-erties of the astrocytic Ca21 signaling toolkit (Berridgeet al., 2000a,b)G-coupled membrane receptors, Ca21</p><p>mobilizing second messengers, ER, Ca21 buffering mole-cules and intracellular organellesthat once fully activatedto produce an intracellular Ca21 wave can be transmittedto an adjacent astrocyte, with a velocity that is independ-ent of the type of preparation used, i.e., independent ofthe morphological differences. Moreover, even consideringthat the extent of ICW spread is vastly larger in cultureconditions than in brain slices, most likely due to the re-stricted extracellular space in the latter, the studies per-formed in cultured astrocytes from different brain regionsdescribed above suggest that the distance of transmissionof ICW is likely related to heterogeneous populations ofastrocytes. Differences in type and number of membranereceptors and gap junction channels, main components ofastrocyte intercellular Ca21 signaling (see following), arelikely responsible for dening boundaries of communicat-ing networks.Although these in vitro studies indicate that astrocytes</p><p>can to some variable extent and degree transmitICWs, the magnitude of the stimuli necessary to triggerthis form of Ca21signaling is usually considerably higherthan would be expected to occur under physiologicalsituation. Thus, the existence and relevance of this formof astrocytic communication for CNS function may bequestioned at least in normal, physiological situations. Inwhole-mount retinas, ickering light stimulation indu-ces Ca21 transients, but not intercellular Ca21 waves inMueller cells of the inner plexiform layer; however, in thepresence of adenosine, light ashes enhance Mueller cellresponses and induce ICW spread between the...</p></li></ul>