Astroglia Nature 2010

8/3/2019 Astroglia Nature 2010

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Oer the past three ecaes or nerstaning o inter-cear conication etween gia has naentachange ro the notion that the are organize as asncti a tinceate ass o ctopas rest-ing ro the sion o ces to the recognition thatthe are organize into networks. Inee, in the 1970sthe ientiication o a arge ner o gap jnctions eto the stateent: Ajacent gia ces, howeer, inc-ing those o aas, are inke to each other gap

jnctions. In this respect the resee to epitheia angans ces an heart sces iers(in From Neuronto Brain S.W. Ker an J.G. Nichos1). This state-ent was rther spporte trastrctra ata p-ishe in an artice with the expicit tite Cell junctions ofastrocytes, ependyma, and related cells in the mammaliancentral nervous system, with emphasis on the hypothesis

of a generalized syncytium of supporting cells2. Sincethen, the ter gia sncti has een extensiese in seera pications, an een recent a reiewreerre to a pan-gia sncti3.

The present Reiew iscsses ata sggesting thatgia, an in particar astroctes, are organize as net-works an conicate throgh speciaize channes,the so-cae gap jnctions. We propose that nerogiaan gioascar interactions sho e consiere ata network ee that is, eon a iaoge etweensinge ces. We hope that this working hpothesis witrigger research that wi ea to a etter nerstaningo nerogia network interactions.

Cx wk

Connexins and gap junctions. Gap jnctions (BOX 1)are expresse extensie in the neros sste. Oneo the irst reports o irect ce-to-ce conicationpresente eectrophsioogica eience that gap jnc-tions aowe transission etween nerons at eectri-ca snapses4. A ew ears ater it was eonstrate thatnon-nerona ces were aso extensie cope ce-to-ce jnctions5. In sseqent ears, the trastrctraasis o gap jnctions was escrie an the connexin(Cx) ai o proteins were ientiie as the oecarconstitents o gap jnction channes (GJCs).

Twent-one Cxs hae een ientiie so ar, aneeen o these hae een etecte in the erteraterain3,68. Each Cx has its own pattern o expression antpica ore than one Cx is expresse in a gien ce

tpe3. Cxs are organize as hexaers eee in thepasa erane that, when associate hea-to-heaetween two neighoring ces, or a GJC (FIG. 1a).Howeer, recent inings hae eonstrate that Cxs canaso operate as heichannes (BOX 2), aowing exchangeo oeces etween the ctopasic an extraceareia912. Heichannes can aso e copose o pan-nexins, a istinct ai o erane proteins that arehooogos to innexins, the GJC-oring proteins ininerterates13.The centra pore o heichannes or GJCsaows the passage o ions (ionic coping) an saoeces (iocheica or etaoic coping), witha ct-o seectiit o aron 1 to 1.2 kDa. Neros

*INSERM U840, Collge de

France, 75005 Paris, France.Department of Biology and

Mathematics, Ecole Normale

Suprieure, 75005 Paris,

France.

Correspondence to C.G.

email: christian.giaume@

collegedefrance.fr

doi:10.1038/nrn2757

Astroglial networks: a step furtherin neuroglial and gliovascularinteractionsChristian Giaume*, Annette Koulakoff*, Lisa Roux*, David Holcman and

Nathalie Rouach*

Abstract | Dynamic aspects of interactions between astrocytes, neurons and the vasculature

have recently been in the neuroscience spotlight. It has emerged that not only neurons butalso astrocytes are organized into networks. Whereas neuronal networks exchange

information through electrical and chemical synapses, astrocytes are interconnected

through gap junction channels that are regulated by extra- and intracellular signals and

allow exchange of information. This intercellular communication between glia has

implications for neuroglial and gliovascular interactions and hence has added another

level of complexity to our understanding of brain function.

neuronglia interaC tions

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NATuRE REvIEWS |NeuroscieNce vOlumE 11 | fEbRuARy 2010 |87

20 Macmillan Publishers Limited. All rights reserved10
mailto:[email protected]:[email protected]:[email protected]:[email protected]


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a b

25m25m 100m

sties hae shown that the seectie copatiiito ierent Cxs or the asse o Cx channes, theirgating properties, seectiit an regation epen onthe natre o their oecar constitents, which has eto the concept o a Cx angage14. Athogh GJCs haeeen extensie stie, ess inoration is aaiae orheichannes (BOX 2).

Connexins in astrocytes. In the at rain, Cx43 (asoknown as GJA1) an Cx30 (aso known as GJb6) arethe ain Cxs in astroctes1518. Their reatie ees araccoring to the eeopenta stage an rain region19.Cx43 is expresse ro ear in eeopent, aron

the tweth a o gestation in rat raia gia processes.As eeopent procees, Cx43 expression increasesan is etectae throghot the rain as inoreac-tie pncta. Cx30 is expresse in astroctes in jenieroents ring the thir postnata week, with a pnctatestaining pattern17,19(BOX 1). Cx30 an Cx43 are cearco-expresse at jnctiona paqes o atre gre at-ter astroctes. Howeer, there are regiona ierences inthe expression o these two connexins, the ajor ier-ence eing that there is no Cx30 expression in astrocteso white atter tracts18. Athogh singe-ce reersetranscription PCR perore in hippocapa astro-ctes has etecte the presence o other Cx RNAs 20,

no intercear conication as assesse e coping experients was osere etweenastroctes o Cx43;Cx30 oe-knockot ice21,22,strengthening the notion that Cx43 an Cx30 are theajor astrogia Cxs. Interesting, as we as their roein GJCs an heichannes, Cxs are inoe in othergia nctions, sch as ahesion23 an oation oprinergic receptors24.

When coparing nerons an astroctes, one has tokeep in in that whereas nerons sa hae oerap-ping enritic ies in aition to axona projections,protopasic astroctes o the gre atter occp errestricte an inepenent spatia territories. Inee,

ase on gia iriar aciic protein (GfAP) i-nostaining, astroctes were initia escrie as steateces with arge interigitations etween the processeso ajacent ces25. Recent, orphoogica anasis oe-ie astroctes in the hippocaps an the cor-tex inicate that the are ore spongior than star-shape an occp separate anatoica oains2628.Conseqent, to coorinate inoration transer in areiae an eicient anner, astroctes nee a strongoait o intercear conication: Cx-eiatepathwas can certain i this nction. Inee, injec-tions o intercear tracers into one astrocte reeaethat hnres o ces can contrite to astrogia

Box 1 | gp jc: wh hy d hw dy hm cy

Gap junctions form aqueous

channels and are sites of direct

intercellular communication. The

term was proposed on a

morphological basis owing to the

gap of ~2 nm that separates

the membranes of adjacent cells,as revealed in electron

micrographs. Gap junction

channels (GJCs) are composed of

connexins (Cxs), which can be

visualized by immunohistochemi-

cal stainings in astrocytes that

express glial fibrillary acidic

protein (GFAP) (see part a of thefigure, with GFAP staining in white

and Cx30 staining in red) to reveal their expression between and within astrocytic domains and at contacts between

endfeet that wrap blood vessels. Connexons are hexameric structures composed of Cx subunits. The connexons of two

adjacent cells dock to form a GJC that allows the intercellular diffusion of small molecules of up to 11.2 kDa and ~1.5 nm

diameter (biochemical or metabolic coupling) and the flow of currents (ionic coupling) when there is a transjunctional

voltage difference. A fluorescent dye injected into one cell will diffuse into adjacent cells if they are coupled by GJCs. In

the experiment illustrated in part b of the figure, biocytin (red) was injected into an astrocyte (white star) in ahippocampal slice from an hGFAPeGFP mouse (in which the expression of enhanced green fluorescent protein is under

the control of the human GFAP promoter). Note that in a single confocal plane, not all eGFP-positive astrocytes are dye

coupled and therefore are not part of the same network.

The lack of specific pharmacological tools111,123,124 requires an alternative, genetic approach, such as Cx-knockout mice

to study the role of astroglial GJCs111. This strategy has already been used in brain slices21,22 and in vivo112. However, as there

are two main Cxs in astrocytes, namely Cx30 and Cx43, double-knockout mice have to be used. Moreover, as Cx43 is widely

expressed in different organs, an astrocyte-targeted Cx43 knockout was designed using an hGFAP promoter-driven cre

transgene. As expected, dye coupling in astrocytes from double-knockout mice was not observed, and hence these mice

allow us to study the function of astroglial networks, for instance in pathological models of epilepsy 21 or hypoglycaemia22.

However, such an approach also has its limits as Cx genes, in particular the gene encoding Cx43, may be important for

regulating brain gene expression125. Alternatively, small interfering RNAs or engineered lentiviral vectors targeting

astrocytes126 could provide other strategies to silence astroglial Cxs in brain slices or in vivo models.

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http://www.uniprot.org/uniprot/P17302http://www.uniprot.org/uniprot/O95452http://www.uniprot.org/uniprot/O95452http://www.uniprot.org/uniprot/P17302


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ab

Hemichannel Intercellulargap junction

Reflexivegap junction

Hippocampus

c d

Barrel cortex

Olfactory glomerulus

networks in the hippocaps20,22,29,30, the cereracortex 31, the inerior coics32 an the striat33.fina, athogh gap jnctions are osere at theinterace etween two neighoring astroctes an atcontacts etween gia eneet that enwrap oo es-ses18,22, inohistocheica stainings or Cx43 anCx30 reeae that their expression is not restricte to

these ocations (BOX 1). This sggests that, in aitionto their roe in intercear conication, Cxs cooperate etween processes originating ro a singeastrocte (FIG. 1a). Sch reexie gap jnctions, areaescrie at the trastrctra ee25, co e parto astroctic icrooains34 an contrite to theirintegratie responses.

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Figure 1 | Atga nnxn an mmnatng ntw. a | Localization and structure of connexin (Cx)

channels in astrocytes. Domains that are occupied by neighbouring astrocytes do not overlap, and intercellular gap

junction channels (GJCs) are located at contact points between neighbouring astrocytes. In an individual astrocyte,

one process can contact another process and form reflexive gap junctions. Alternatively, in defined situations(BOX 2), Cxs can also operate as hemichannels at the surface of the cell membrane to exchange information with the

extracellular space. As astrocytes express mainly two Cxs (BOX 1), several combinations of Cx43 (blue) and Cx30 (red)

can be encountered: both GJCs and hemichannels can be made of only one Cx (homomeric channels) or of a

combination of two Cxs (heteromeric channels); GJCs can also be heterotypic that is, composed of two different

homomeric or heteromeric hemichannels. Parts b illustrate the organization of different astroglial networks. b | In

the hippocampus the layer of pyramidal neurons (red) limits the number of astrocytes in this compartment and

affects their morphology22,43. | In the somatosensory cortex the distribution of astrocytes is homogeneous but

Cx30 and Cx43 are differentially expressed in barrels and septa: they are highly expressed in barrel astrocytes (dark

blue) and weakly expressed in septal astrocytes (light blue)31. | In the olfactory bulb the cell bodies of glomerular

astrocytes are located at the periphery whereas their processes have a centripetal orientation142,143. In and

astroglial communication is focused towards the centre of the functional unit, which enhances communication in

neuronal compartments31. The red triangles or circles indicate the location of neuronal somata in the indicated

structures but do not reflect their density or size.



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Pp f wk

besies iniia astroctic oains, conicatingnetworks constitte another ee o spatia organiza-tion o these ces. Soe ces to the res that goernsch ticear organization are proie recentinings.

Dye-coupling experiments.De-coping experients(BOX 1), in which e is injecte into one ce an itsintercear ision is onitore, inicate that orethan 80% o a cope cesare astroctes, ientiie sing either speciic astrocte arkers or transgenicice that carr aee astroctes (hGfAPeGfP ice,in which the expression o enhance green ores-cent protein (eGfP) is ner the contro o the hanGfAP prooter, with GfAP eing a arker or astro-ctes)20,22,35,36. Howeer, these inings o not exce thepossiiit that heterotpic gap jnctions a occasion-a occr etween astroctes an either nerons3739 oroigoenroctes40,41. Interesting, certain interactionsetween astroctes an oigoenroctes co e inketo the expression o astrogia Cxs, as eetion o Cx43an Cx30 is associate with seination as we as tohippocapa acoation42. Neertheess, athogh the

existence o sch heterotpic jnctions has een eon-strate, the are rare an iite to certain rain regionsan eeopenta stages. moreoer, astrogia networksexhiit a egree o seectiit, or exape in the hip-pocaps o hGfAPeGfP ice seera eGfP-positieces (which are asse to e astroctes) are ocatewithin the coping oain o an injecte astrocte, tare not e cope43(BOX 1). Aso, in the soatosensorcortex o roents, astroctes that are ocate etweenarres are weak or not cope, whereas copingo astroctes within a arre is extensie an orientetowars the arres centre31 (FIG. 1c). In the oactor, e-coping experients hae shown restricte

conication etween intra- an extragoerarastroctes44 (FIG. 1d). Conseqent, in aition to ier-ences in the expression o receptors, transporters an ionchannes45, Cx-eiate coping proies a criterionwith which to iscriinate spopations o astroctesin one region.

Factors influencing the shape and extent of astrocytenetworks. The extent an shape o these astrocticnetworks are ariae an ner the contro o seeraactors, incing the eeopenta stage. Inee,astrogia coping increases in the hippocapsan the cortex ring the irst postnata weeks31,36, apropert that is proa inke to the onset o Cx30expression an the increase in Cx43 ee. b contrast,the ner an size o Cx43 an Cx30 paqes as weas the ee o coping ecine in the ageing rain 46,47.Heterogeneit in Cx43 an Cx30 expression etweenrain regions an een in a singe region17,18,31,48 aaso expain ierences in the extent o e coping 31.for instance, astroctes are ore e cope in CA1

than in CA3 o the hippocaps30. The nctionareeance o this ierence in coping has not eteen eicite. Howeer, as CA1 is poor sppie withcapiaries copare with CA3 (ReF. 49), it has eenpropose that the sstantia astrogia coping inCA1 is attritae to the nee to cone etaoicsignas across this ess ascarize region (see eow).Athogh the coping area o an astrocte is in generaspherica, in soe cases it is asetrica, as shown inpper cortica aers or CA1 (ReF. 43). In these cases, theshape o astrogia networks rests ro the organi-zation o nerona aers an is correate to the Cxexpression pattern (FIG. 1b). moreoer, the shape anextent o astrogia networks can e tight inke tonerona nctiona nits, as recent reporte or thearres in the soatosensor cortex 31 an or oac-tor goeri44(FIG. 1c,d). Thereore, astrogia net-works see to coincie with nctiona nits o thenerona network.

Cx dc pp f p jc

Selectivity of gap junction channels in astrocytes. Toeciate the potentia roe o Cxs in the phsioogan pathoog o the neros sste, it is iportantto nerstan the properties o GJCs that goern theirseectiit an intercear exchange. Cx channes haetraitiona een iewe as poor seectie channes

that are pereae to ions an sa oeces. As GJCsare pereae to secon essengers, the are consiereto e eiators o intercear signaing 50. Howeer,on recent has the pereaiit o GJCs to enog-enos ioactie ctopasic oeces een teste, as itwas reaize that this oes not necessari correate withpereaiit to orescent tracers.

The res that ictate the aiit o a oece topereate throgh GJCs are copex. The pereaiito GJCs is not a sipe nction o the oecar weightan size o the exchange oece it epens asoon the oeces shape, charge an speciic interactions(eectrostatic or ining) with the Cxs in the channes.

Box 2 | Hmch c cb pc phwy

Under certain conditions, connexins (Cxs) can operate as hemichannels, allowing

exchanges between the cytoplasm and the extracellular medium11,12,127. Under basal

conditions, the hemichannels that have been described in various cell types are

inactive, maintaining cellular integrity11. In astrocytes, hemichannels become activated

under several experimental conditions, such as Ca2+-free medium, metabolic inhibition,

moderate increase in intracellular Ca2+ concentrations or pro-inflammatory treatments,

resulting in their opening, as indicated by various dye-uptake assays. Interestingly,astrocyte hemichannels were shown to be permeable to gliotransmitters such as

glutamate, ATP128,129, glucose130 and glutathione131,132. Thus, hemichannel activation and

ATP release may support the propagation of intercellular Ca2+ waves88,133. Alternatively,

hemichannels can affect nearby neuronal activity throughthe release of

gliotransmitters or can affect neuronal survival through the release of neuroprotective

or deleterious agents.

Cx43 and Cx30 have been reported to form functional hemichannels in HeLa

transfected cells134 indicating that both Cxs can account for membrane

permeabilization. However, so far it is not known whether mixed Cx43 and Cx30

hemichannels operate in astrocytes. Another family of membrane proteins, the

pannexins might form hemichannels (but not gap junction channels13) in astrocytes.

Nevertheless, except in the case of Bergmann glia135, their in situ expression in glia

remains to be proved. Sequence analysis of pannexins indicates that they have a

transmembrane topology similar to that of Cxs but a great divergence in primary

sequence13,136

that might explain their distinct unitary conductance and pharmacology.

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Cx43 channes are seectie or seera enogenosoeces, incing secon essengers (ccic AmP,inosito-1,4,5-trisphosphate (InsP

3) an Ca2+), aino

acis (gtaate, aspartate an tarine), nceoties(ADP, ATP, CTP an NAD), energ etaoites (g-cose, gcose-6-phosphate an actate), sa pepties(gtathione) an RNA (24er)51,52, t not or argeoeces, sch as nceic acis, proteins an ipis.less ata are aaiae on the ioactie oeces thatcan pereate throgh Cx30 GJCs, t ATP, InsP

3, aspar-

tate, gtaate, gcose an actate hae een reporteto o so52. In aition, Cx30 channes hae een shown toe seectie or cations oer anions53. Athogh GJCpereaiit has oten een thoght to aintain hoe-ostasis etween cope ces, ierences in the rateo jnctiona x can aect the spee o ision anthe eectie concentration o secon essengers (schas InsP

3or cAmP) that hae a restricte ctopasic

ision an ietie. As ost o the signaing o-eces are charge at phsioogica pH, their isionthrogh GJCs occrs aong an eectrocheica graient.

Howeer, it is conceiae that the cationic seectiito Cx30 channes co generate poarize pathwas ointercear signaing in astroctes53.

Voltage dependence of GJCs. The transjnctiona antranserane otage epenence o GJC conct-ance can aso act as a seectiit iter to iit an co-partentaize the ision o ioogica signaingoeces. This is reeant to certain pathoogica con-itions, as iscsse ater. Hootpic Cx30 an Cx43channes an heterotpic Cx43Cx30 channes are ot-age epenent54 (t see aso ReF. 55 or astroctes).There are two ines o eience or this: irst, oth Cx30an Cx43 channe conctances are epenent on trans-erane otage; an secon, Cx30 is ore sensitiethan Cx43 to transjnctiona otage sensitiit, coner-ring a prononce rectiication in heterotpic chan-nes56. These properties o GJCs a aow ces to isoatethesees ro epoarize, aage ces in patho-og. Interesting, een when phsioogica conitionsare raatica atere to iic pathoogica sitations,GJCs (or at east part o the) reain open57; howeer, itis not known whether their seectiit is oiie.

th wk

The network organization o astroctes can e se toeier pharacoogica or oecar toos to speciic

popations o conicating astroctes. Whoe-cepatch-cap o a singe astrocte aows the iasis othis astrocte, an oeces pereae to GJCs wi i-se in the associate network. Apping the Ca2+ cheatorbAPTA with this strateg showe that Ca2+ signaing inastrogia networks aects hippocapa heterosnapticepression58. It was aso shown that astrogia networksspp gcose an actate to sstain hippocapa sn-aptic transission22, an sties inestigating the roe oInsP

3in hippocapa nction sggeste that this o-

ece can ince gtaate reease ro gap jnction-cope astroctes, triggering transient epoarizationsan epieptior ischarges in CA1 praia nerons59.

In the tre, this network propert co e expoiteto sience speciic oecar targets in a popation oastroctes appication o GJC-pereae iocheicatoos or sa interering RNAs60 in Cx-connecte net-works. Sch a irecte pharacoogica strateg coaow testing o the ipact o atering speciic signa-ing coponents (or exape kinase or phosphatasepathwas, esicar secretion an ionic channes) in apopation o astroctes on nerona signaing.

n cvy hp wk

The pereaiit o GJCs is regate seera actorsthat act on nerona erane receptors (TABLe 1). btoes nerona actiit regate conication in astro-ctic networks?

Neuronal activity effects on astrocytic dye coupling.On a ew sties hae aresse this qestion. Decoping is increase in cereear an striata astroctesthat were co-ctre with nerons61,62 an in gia ceso the rog optic nere when nerons are stiate63.

The nering echaniss reain arge nknown,t recent sties hae she soe ight. Eeate eeso extracear K+ epoarize astroctes an increase thepereaiit o gap jnctions64, an eect that is poten-tia eiate phosphoration o Cx43 caci/caoin-epenent protein kinase II65. The eectso gtaate are ore copex an epen on the rainarea stie (cortex64, striat61,66, hippocaps67 orceree68), the tpe o preparation se (ctresor rain sices) an the tpe o gia receptor inoe.

Neuronal activity effects on GJC permeability tobioactive molecules. A o the aoe sties hae ines-tigate the eect o nerona actiit on astrogia GJCpereaiit to passie es or tracers. bt what aotioactie oeces? Gcose traicking throgh GJCswas recent stie in hippocapa sices sing o-rescent gcose eriaties22. This st eonstratethat gtaate reease ro nerons increases gcosetraicking in astrogia networks actiating AmPA(a-aino-3-hrox-5-eth-4-isoxazoe propionicaci) receptors. As hippocapa astrocte networksack AmPA receptors69,70, it reains ncear whethergtaate itse or a ownstrea eector o postsnapticAmPA receptors regates gcose traicking throghastrogia GJCs. Srprising, this actiit-epenentregation o gcose traicking is not osere with

passie es or tracers. This sggests that, at east in thehippocaps, gtaatergic actiit oes not regateGJCs t triggers a oca energ ean that generates aision graient or gcose to e traicke to the siteso high nerona ean.

acyc wk fc

Astroctes are now consiere to e actie eeents o therain circitr: the integrate nerona signas, exhiitCa2+ excitaiit an process inoration71,72. Inee, Ca2+signaing in actiate astroctes has een proposeto trigger the reease o an neroactie oeces,nae giotransitters, sch as gtaate, ATP an

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d-serine, which can oate nerona excitaiit,snaptic actiit an pasticit. These inings initiatethe exciting concepts o the tripartit synaps, astrocteCa2+ excitaiit, giotransission an astroctic esic-ar reease7377, soe o which (sch as Ca2+-epenentgiotransission, esicar or sosoa reease) are sticontroersia. Aternatie approaches, incing the seo transgenic ice, ight resoe these controersies sing ore speciic oecar toos to seectie targetastroctes7881.

up to now, the inoeent o astroctes in CNSnctions has ost een consiere on a singe-ceasis rather than as an actie partnership etween cepopations. The atter iew is spporte the networkorganization o astroctes an their pereaiit tosignaing oeces.

Here we posit that, owing to the proxiit o astro-cte gap jnctions an nerona snapses25(FIG. 2a,b),astroctic networks co e actie associate witha grop o snapses. Hence, speciic astroctic net-works, thanks to their pereaiit to the potentiagiotransitters gtaate, gtaine82 an, possi,d-serine, co coorinate the actiit o oca grops

o snapses (FIG. 2c,d). In aition, the coorinatereease o giotransitters ro astroctes o one net-work co span a arge area an hence co aectnerona network actiit. This working hpothesiscan e teste insing astroctic networks withoeces inoe in giotransission an singCx-knockot ice. In act, recent sties hae shownthat, owing to their Ca2+-signaing properties, astro-gia networks in the hippocaps are inoe in het-erosnaptic epression: ATP is reease astroctes

eon the area o act iate snapses an conerteinto aenosine, which cases inhiition o transitterreease in near snapses58. In aition, hippoca-pa astrogia networks that were inse with InsP

3

reease gtaate that in trn triggere neronaepoarizations an epieptic ischarges59. moreoer,astroctic networks were aso reporte to increase thethresho or generation o epieptic ischarges con-triting to the ering o extracear K+(ReF. 21).In sar, athogh these ata sggest that astrogianetworks hae a roe in regating nerona networkactiit in the hippocaps, this reains to e irecteonstrate.

Table 1 | r f p jc pmby bw cy

M et et n GJc ntn Tnq r

Endogenous substances (or analogues)

Mouse cerebellum Kainate Junctional current recordings in Bergmann glia 68

hGFAPeGFP mousehippocampus

NMDA application associatedwith neuronal action potentials

Dye coupling (biocytin) 67

Rat hippocampus Endothelins Dye coupling (biocytin) 20

Junctional current recordings 145

Drugs that have an effect on neuronal activity

Mouse olfactory glomeruli TTX Dye coupling (sulforhodamine B) 44

Mouse hippocampus TTX Dye coupling (2-NBDG) 22

No effect Dye coupling (biocytin or sulforhodamine B) 22

Mg2+ + picrotoxin (epilepticactivity)

Dye coupling (2-NBDG) 22

No effect Dye coupling (biocytin or sulforhodamine B) 22

CNQX Dye coupling (2-NBDG) 22

CNQX + CPP (in epilepticactivity or not)

Stimulations

Frog optic nerve Nerve impulses Dye coupling (Lucifer Yellow) 63

Conscious rat inferiorcolliculus

Acoustic stimulation Microinfusion

([1-14C]glucose)

92

Microinfusion

([U-14C]lactate)

92

Microinfusion

([U-14C]glutamine)

92

Others

Rat striatum Ethanol Dye coupling (Lucifer Yellow) 146

Note that only brain slices and in vivo experiments are listed here; data obtained from cell cultures were previously reviewed and discussed147. CNQX,6-cyano-7-nitroquinoxaline-2,3-dione; CPP, 3-(-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid; eGFP, enhanced green fluorescent protein; GJC, gap junctionchannel; hGFAP, human glial fibrillary acidic protein; NMDA, N-methyl-d-aspartate; TTX, tetrodotoxin.

Tripartite synapse

A concpt in synaptic

physiology basd on th

xistnc of communication

btwn th pr- and

postsynaptic trminal and a

surrounding astrocyt.

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a b

c dTripartite synapse Synapses and neuroglial networking

1 1

4 4

2 2

3 3

5

acy wk cb y ppyProcessing o inoration in the rain is etaoi-ca expensie. Inee, the rain acconts or on 2%o or o ass t 20% o or oxgen an gcose

consption83,84. The roe o astroctes in the spp oenerg sstrates to nerons is one o their oest knownnctions. Astroctes are ocate at a strategic positionetween oo capiaries an nerons (irst reporte inthe nineteenth centr85) an hae a ke roe in co-ping nerona actiit to the se o gcose in the rain(nurovascular coupling)86.

Neuronal glutamate release stimulates glucose supplyby astrocytes. Astroctes proie nerons that reeasegtaate with etaoic sstrates, as nerona acti-it is inicatie o an increase in energ ean. Thisactiit-epenent echanis inoes Na+-cope

gtaate ptake in astroctes an actiation o theNa+/K+ ATPase, which triggers gcose ptake rothe oo an its gcotic processing, resting in thereease o actate ro astroctes (FIG. 3a). lactate, as weas gcose, can in trn e se as e nerons to eettheir energ ean84. In this oe, aso cae theastrocytnuron lactat shuttl, astroctes are consiereas singe entities. Howeer, recent gtaate reeasero nerons has aso een shown to generate etaoicwaes in ctre astroctes, resting in coorinateptake o gcose gap jnction connecte astroctes87,there apiing the etaoic response.

Glutamate increases glucose diffusion through GJCs.This apiication sste, in which Na +has eenpropose as a secon essenger in neroetaoiccoping, reqires intercear Ca2+ waes to triggergtaate reease ro ctre astroctes. Interesting,the network organization o astrogia a aect theastrocteneron actate shtte (FIG. 3a), as interce-ar caci waes are epenent on Cx channes88

(FIG. 3b). Whether Ca2+ waes propagate throgh astro-cte networks in situ an in vivo ner phsioogicaconitions reains ncear89, t this pathwa ight einoe in pathoogica conitions intercear Ca2+waes in astroctes hae een reporte in vivo an inose oes oAzheiers isease90.

Gcose an soe o its etaoites, sch asactate, traic throgh the GJCs o astrogia networks, asshown in ctres91, sices22 an in vivo92. In hippocapaastrogia networks, this traic is increase gtaatereease an actiation o nerona AmPA receptors tnot astrogia gtaate transporters22. Snaptic orethan spiking actiit sees to contro this gcose tra-icking in astrocte networks. Interesting, this is asothe case or neroetaoic coping in the isa cor-tex93 an or oor-eoke oxiatie etaois in theoactor 94. Gcose traicking that is epenenton nerona actiit co aso sstain nerona sriain pathoogica conitions that ater energ proction,sch as hpogcaeia, anoxia or ischaeia, in whichGJCs are sti nctiona57.

Thereore, gtaatergic snaptic actiit enhancesoth gcose ptake an gcose traicking in astrogianetworks an ight sere to eicient spp energetaoites to reote sites o high nerona ean(FIG. 3bd). Whether on gtaatergic nerons, or asoista GAbA (-ainotric aci)-ergic an choin-

ergic nerons, are sppie these astrogia networkpathwas reains nknown. Inee, athogh astroctesaso take p GAbA throgh Na+-epenent transport-ers, inhiitor actiit has not een shown to e copeto the se o gcose95.

What is the roe o coorinate astrogia etaoicnetworks? first, it is not rare in ioog or ore than oneechanis or oece to i an essentia nction,an thereore gcose traicking throgh GJCs ighte an aternatie or parae pathwa to gcose ptake.Secon, these pathwas ight ensre that astroctes caneet the increase gcose ean resting ro highnerona actiit. frtherore, when gcose ean

Figure 2 | Tatt yna an nga ntw: b nqn

ynat tanmn. a,b | Electron micrographs showing the closeness of two modes

of communication: a synapse for neuronal communication and gap junctions between

astrocytes. Note that pre- and postsynaptic elements (pink) are surrounded by astrocytic

processes (blue). Immunostaining with a Cx30-specific antibody indicates the presence

of a gap junction (arrow) between two astrocytic processes. , | The role that astrocytic

processes (blue) could have nearby a glutamatergic synapse (red). In , only neuroglial

interactions occurring at the tripartite synapse are taken into consideration. The

different steps involved in this dynamic interaction are: the release of neurotransmitter

(step 1), its action on receptors and transporters in astrocytes (step 2) and the release of

gliotransmitter (step 3) that in turn influences neuronal activity. In , in addition to these

three steps, glutamate that has been taken up by a neighbouring astrocyte, and also its

derivative, glutamine, can diffuse and permeate through gap junction channels (step 4)

of astrocytic networks (yellow stars). This trafficking may result in subsequent release of

gliotransmitter at a distant synapse (step 5) or even extrasynaptic sites and hence affect

the activity of the underlying neuronal network. Images in part a are courtesy of

C. Genoud and E. Welker, University of Lausanne, Switzerland.

Neurovascular coupling

Th link btwn nuronal

activity and nrgy supply

from blood flow, in which

astrocyts participat.

Astrocyteneuron lactate

shuttle

Activity-dpndnt fulling of

nuronal nrgy dmand,

consisting of glucos uptak at

astrocyt ndft, its glycolysis

and th dlivry of lactat to

nurons by astrocyts.

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Astrocytes CapillaryNeurons

ba

dc

Glucose

Lactate

Glutamate Glutamate

ADPATP Glucose

K+H+

K+

Na+Na+ ATPADP

Glucose

Glucose Lactate

Glucose Lactate

Lactate

Glutamate

Glutamate

Glycogen

Glycogen

Glycogen

excees spp, or exape in sitations o atere s-strate aaiaiit (sch as in hpogcaeia, ischaeiaan gcose transporter eicienc), astroctes can con-

ert their gcogen stores into gcose an actate, which

can sprea throgh GJCs to e ista nerons. Thir,athogh eer capiar is a oca sorce o gcose, thecapacit to take p gcose an eier it to neronsa ier etween astroctes in a gien rain area. Thecapacit or gcose ptake wi epen on the capiarcoerage astroctic eneet, their ensit o gcosetransporters, the astrogia etaoic achiner an thestrength o nerogia interactions (which is eterine the ensit o receptors on astroctes an astrocticcoerage o nerons). These paraeters are ike to eheterogeneos aong astroctes, an thereore astrocticnetworks a constitte a pathwa to eqiirate gcosespp to nerons.

acy wk d bd fw cAstrogia eneet that enwrap oo esses are char-acterize high ees o Cx expression18,22. As a con-seqence, gap jnctiona conication etween

astroctes is aore cose to the ascatre 22.Eerging eience ipicates an

increase in intra-

cear Ca2+ concentrations ([Ca2+]i) in astroctes in

either asoiation or asoconstriction96,97, epeningon the natre o the signa that triggere the [Ca2+]

i

increase. Inee, a oca [Ca2+]iincrease in a singe

periascar igit spreas throghot the entire processo the astrocte, incing the enoot, an then propa-gates to ajacent eneet98. As Cx channes contriteto the intercear propagation o Ca2+ waes88in vivo99an in pathoogica sitations90, it is sggeste that theparticipate in the regation o oo ow increasingthe ner o eneet inoe in the response. As the

Figure 3 | Atga mtab ntw tan nna atty. Astroglial gap junctions contribute to metabolic

pathways in the brain. a | The mechanism underlying glutamate-induced glycolysis during glutamatergic synaptic activity.

In the classical astrocyte-neuron lactate shuttle144, in addition to the direct extracellular route, glucose is taken up by

astrocytes in response to glutamatergic neuronal activity that is followed by glutamate uptake in astrocytes. The energy

required for glutamate uptake is provided by glucose metabolism leading to lactate production that is delivered to

neurons. b | The contribution of the astrocyte network to the glucoselactate shuttle shown in a. Note that in the example

shown, glutamate spillover after presynaptic release stimulates a distant astrocyte (dark blue), close to a blood vessel. The

metabolic cascade illustrated in a applies but is not detailed for reasons of clarity. After glucose uptake from the blood by

the dark blue astrocyte, glucose and its metabolites permeate gap junction channels and reach adjacent astrocytes (lightblue) that are in contact with the active neurons and provide these with energy substrates. Parts and show the

contribution of astroglial metabolic networks to synaptic activity. | Astroglia networks with closed gap junction channels

do not support increased neuronal activity (thick red lines and symbols) (although they still get extracellular glucose

directly from their transporters) and with time, the activity of neuronal networks can be reduced owing to a minimal

energy supply (thin red lines and symbols). | By contrast, in the presence of an open metabolic network (dark to light

blue), an intercellular route is provided, allowing the trafficking of energy substrates from their source, blood vessels, to

the site of high energy demand and use, neurons (red triangles). Part a is modified, with permission, from ReF. 144 (1999)

International Union of Physiological Sciences and the American Physiological Society.

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proction o asoactie oeces is Ca2+-epenent,their eicac in oo ow contro is expecte to ereate to the extent o the periascar propagation oCa2+ signaing throgh eneet o the sae astrocteor ierent astroctes connecte reexie or inter-cear gap jnctions, respectie100. Aitiona,heichannes co e inoe in the regation ooo ow, as the hae aso een propose to con-trite to the propagation o intercear Ca2+ waesthrogh ATP reease88.

a wk b dyfc

In pathoogica sitations, ro acte injr to nero-egeneratie isease, astroctes nergo proon or-phoogica an nctiona reoeing that is epenenton the tpe o inst or pathoog, tiing an the is-tance ro the site o injr101. Dring this process, rac-tiv astrocyts can ose their non-oerapping oains102.for exape, ater tipe epieptic seizres the proc-esses o neighoring astroctes interigitate, eaing toixe territories. Sch reoeing at the singe-ce

ee is ike to hae an ipact on astrogia networkorganization.

In aition, changes in Cx expression hae eenreporte in ierse pathoogica sitations that aaso aect the extent o astrogia networks. (TABLe 2;Sppeentar inoration S1 (tae)). In genera, inost neroegeneratie iseases an in ischaeia, reac-tie astroctes hae increase ees o Cx43 expression,athogh this a aso rest ro the internaization ogap jnctions103 an hence oes not necessari reectan increase in the ners o GJCs or in astrogia net-working. moreoer, in rain injr, changes in the eeo Cx expression are epenent on the proxiit o thereactie astroctes to the aage site104106. In epiep-tic tisse, ecrease, nchange an increase Cx43expression hae een reporte (TABLe 2; Sppeentarinoration S1 (tae)). These contraictor rests ain part e e to the iersit o epieps oes orexape, acte erss chronic an aso to the ra-tion o seizres.

What are the conseqences o atere Cx expressionees or the nction o astrogia networks? most othe sties to ate that hae exaine the expressionan nction o astrogia Cxs in a pathoogica contexthae se ctre oes that ocs on on seecte sig-nas an o not reproce a eents occring in vivo ina chronoogica anner. In situ oes hae starte to

proie expressionnction correations or astrogiaCxs. for exape, in rain tisses ro patients withAzheiers isease, the expression o Cx43 is increasein reactie astroctes srroning aoi paqes107.Accoring, in ose oes o Azheiers isease, anincrease in e coping etween cortica astroctes wasrecent reporte47, an intercear Ca2+ waes, initiatein astroctes at the peripher o aoi paqes, wereshown to propagate oer onger istances than in con-tro anias90. In epieptic sitations, an increase in Cx43expression an gap jnctiona conication wasescrie in hippocapa organotpic ctres108.Interesting, proonge exposre to Cx43-ietic

pepties attenates epieptior actiit, inicatingthat enhance coping in astrogia networks ightspport or trigger epieptic actiit109. b contrast, in aose oe o teros scerosis copex that exhiitsepieptic-ike seizres, Cx43 expression is rece ane coping is ipaire110. Hence, the roe o astro-gia networks in epieptic sitations reqires rtherinestigation.

What are the conseqences o astrogia networkchanges or nerona nction an/or sria? Twostrategies hae een aopte to inestigate this qes-tion111. One is a pharacoogica approach sing agents(sch as carenoxoone an octano) that ock GJCs.Howeer, the rests otaine are iict to interpret:irst, ost pharacoogica agents are not speciic anhae sie eects on nerona actiit; secon, ostinhiit a GJCs, an thereore the reatie contritionso nerona an gia gap jnctions cannot e iscrii-nate; an thir, ost ock heichannes as we asGJCs an o not aow their respectie roes to e istin-gishe. becase o these iitations, aternatie strate-

gies, sch as sing Cx-knockot ice or oecar toos,were eeope. Howeer, ost o the rests o thesesties, which ain concern acte injr (ischaeiaan traa), are controersia (Sppeentar inora-tion S2 (tae)).

Gien the roe o gap jnctions in the ering oions, ong-range signaing an exchange o sa o-eces in astrogia networks, a neroprotectie roe orastrogia GJCs has een propose. Howeer, it reainscontroersia whether enhance coping throgh GJCsis eneicia or injrios ner pathoogica conitions.Soe sties hae propose that Cx43-containing GJCsor heichannes a hae a roe in nerona sriaater ischaeia. first, Cx43-knockot ice exhiit aarger inarct oe than wi-tpe ice ater inceischaeia112115. moreoer, it has recent een shownthat ater hpoxic preconitioning, Cx43-containingheichannes pa a ke part in neroprotection.These heichannes reease ATP, which in trn is rap-i conerte into the potent neroprotectie agentaenosine112.

b contrast, gap jnctiona conication in astro-ctes can propagate an api ce injr aowingintercear ision o eath signas that ki ajacentces116. Sch a staner eect co accont or sec-onar eects at sites istant ro the rain injr atercerera ischaeia. Inee, in organotpic hippocapa

sices sitte to hpoxic injr, hpogcaeic injror traatic inst, treatent with Cx channe ock-ers or Cx43-ietic pepties ecrease ce eath117,118.Aso, in ex vivo an in vivo oes o spina cor injr,the appication o ietic pepties that sppress tran-sient Cx43 pregation ater traa reste in a rec-tion o nerona eath an/or aage sprea119,120. Asietic pepties preent actiation o heichannes ta aso, ater onger exposre, preent their ocking toor GJCs109, inhiition o one or oth o the nctionso Cx43 channes that is, their nctions as heichan-nes or GJCs a e inoe in the protectie eectosere.

Reactive astrocytes

Astroglia that, aftr brain

injuris or during pathology,

ar charactrizd by functional

and morphological changs

that can b associatd with cll

migration and prolifration.

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Cc d ppcv

It is now cear that astrogia networks, ike neronacircits, hae tipe ees o copexit. first, co-nication etween astroctes is aore in speciicrain regions that are characterize copartenta-ize nctiona nerona nits, sch as the arre cortex31or the oactor goeri44. Secon, gap jnctiona co-nication is controe enogenos copons,incing nerotransitters, an thereore epenson nerona actiit(TABLe 1). Thir, the pereationthrogh GJCs o inactie tracers oes the aw o pas-sie ision, which is not the case or enogenos io-ogica actie oeces22. Inee, seera paraeters(ietie, ering ining to intracear sites anregeneratie processes) inence the traicking o io-actie oeces throgh GJCs. Ths, the res goern-ing intercear traicking o these oeces throghGJCs are ike to e ore copex than or es22, anthereore the ner o astroctes that are nctionacope or a gien ioactie oeces is expecte toe saer than or a e. Astrogia networks are iketo e inepenent ro each other an are proa notas eaorate as nerona circits in ters o size an thespeciicit o their connections. Howeer, it is concei-ae that their shape an extent ar with tie an theactiit o their enironent.

The concepts o the tripartite snapse an o non-oerapping territories o singe astroctes are essentia

or or nerstaning o naic nerogia interactions.Howeer, the existence o astrogia networks a extenthe nerogia iaoge aowing inoration process-ing an integration ro a arge ner o nerons.Aso, astrogia networks ight hae a roe in proiingetaoites to reote sites ring high nerona eanan in ering ion or nerotransitter concentrations.Sch nctions are ike to e iportant in pathoogicasitations, when nerona hperactiit or exape,in the case o epieps conses ore energ aneas to increase concentrations o K+ an gtaatein the extracear space. Interesting, at the ee o thesinge ce an in the particar context o the tripartite

snapse, astroctes are thoght to oost nerona actiit

reeasing gtaate121,122. b contrast, when consiereat the network ee, especia ring episoes o highnerona actiit, astrogia hae een shown to attenatenerotransission ering srps K+ (or exa-pe, to rece epieptic ischarges21) an reeasing ATP(or exape, to proce neroprotectie aenosine aninhiit presnaptic nerotransitter reease112). In osto the rain pathoogies or injries that hae een st-ie sing ania oes, changes in Cx expression annetwork coping hae een reporte (Sppeentarinoration S1 (tae)) that hae eneicia or eeterioseects. more sties that coine expression an nc-tion anasis are reqire to nerstan the copex roeo astrogia Cxs in rain pathoogies.

An iportant qestion is aso whether astrogianetworks aect nerona actiit. So ar, this qestionhas een rather iict to aress owing to the ack ospeciic toos or sting astrogia Cx channes (BOX 1).moreoer, on a ew sties hae inestigate whichoeces pereate throgh GJCs in vivo ner phsi-oogica conitions an what nctiona signiicance thistpe o intercear signaing has.

matheatica oeing o nerogia interactionsco hep to eterine the roe o inepenent astro-ctes an astrogia networks in this iaoge (BOX 3).Seera sties hae inee attepte to reprocein silico astrogia Ca2+ signas an responses to nero-

na actiit. b contrast, er ew sties hae oeethe eeack o astroctic actiit on nerons. frtheroeing attepts co propt signiicant aancesin or nerstaning o nerogia interactions.

Deects in astrogia Cxs an thereore in the exchangeo inoration at the network ee hae een reportein seera neroogica pathoogies, t it reainsnknown whether these changes are the case or theconseqence o nerona snction an eath. Newpharacoogica an genetic approaches that controthe expression an nction o astrogia Cx channesight proie answers to these qestions111. In aition,the ientiication o the oeces that can pereate

Table 2 | Ch cx xp cd wh phc h Cns

Ban atg an nj et n nnxn xn et n nnxn ntn

Neurodegenerative diseases Cx43 IR in AD, PD and HD

Cx43 IR, protein and mRNA levels in EAE

Dye coupling in AD

NT

Epilepsy , unchanged orCx43 IR, protein andmRNA levels, according to animal models and

seizure duration

anddye coupling

Ischaemia or no change in Cx43 protein and mRNACx43 dephosphorylationCx43 IR redistribution

dye coupling

Autism Cx43 protein NT

Pain Cx43 IR NT

Excitotoxic injury Cx43 and Cx30 IR at zone of neuronal deathCx43 and Cx30 IR at periphery

NT

Details and references are presented in Supplementary information S1,S2 (tables). AD, Alzheimers disease; Cx, connexin; EAE,experimental autoimmune encephalomyelitis; HD, Huntingtons disease; IR, immunoreactive; NT, not tested; PD, Parkinsons disease.

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throgh GJCs represents another iportant chaengeor nerstaning the phsioog o astrocte net-works. Inee, the ee o Cx expression in astroctesis niqe in the neros sste an certain pas a

crcia part in their contrition to rain etaoisan processing. The existence o astrogia networks haspropte s to reconsier nerogia interactions at aore integrate ee.

Box 3 | th why d hw f md wk

Modelling approaches (biophysical models and mathematical analysis) offer an alternative method to understand how

astrocytes contribute to information processing in CNS function and dysfunction. Two levels of interaction can be

considered: the single-cell level, with the concept of the tripartite synapse137, and the network level. Here, we briefly

illustrate emerging concepts by focusing on glutamatergic transmission and the permeability of astroglial networks to

Ca2+, inositol-1,4,5-trisphosphate (InsP3), glutamine and glutamate.

Combining classical equations for the neuronal voltage (Hodgkin Huxley equations) and the Li-Rinzel model to account

for the Ca2+

InsP3 signalling in astrocytes138

has allowed several predictions to be made concerning the tripartitesynapse, such as persistent neuronal spiking occurring if glutamate receptors are overexpressed in astrocytes139 or Ca2+

oscillations persisting in astrocytes even when neuronal activity is minimal140. At the network level, it is conceivable that

coupling between astrocytes will interfere with neuronal activity. Under the assumption that both Ca2+ and glutamate

can be redistributed and dissipated throughout astroglial networks, both signalling molecules might ultimately

contribute to neuronal activity far away from the initial source. Several examples of a neuronal activity dependence of

gap junctional communication in astrocytes suggest that the sphere of influence of astroglial networks on neuronal

synchrony can vary. We propose that for low neuronal spiking frequencies, moderate glutamate release from restricted

astroglial networks might lead at proximal sites to synaptic depression through the activation of extrasynaptic

metabotropic glutamate receptors, as astrocytes first contact extrasynaptic sites77,141 and consequently desynchronize

neurons. However, at a higher frequency, larger glutamate release from extensive astroglial networks could reach distal

sites and activate postsynaptic AMPARs (-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors) andNMDARs (N-methyl-d-aspartate receptors), resulting in an increase in neuronal activity. Conversely, this model predicts

that when the extent of glutamate release from astrocytic networks decreases, distal synapses should desynchronize,

rendering astrocytes unable to modulate large neuronal networks.

Future models should address two aspects of neuronal activity: first, the contribution of astroglial networks to a singlesynapse, and second, the possibility of synchronization or at least coordination at a slow timescale between several

synapses. As several of the parameters mentioned above are likely to affect pathological situations, a modelling

approach could ultimately be used to determine the contribution of astroglial networks to dysfunctions in neuronal

activity, such as during epileptic seizures.

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AcknowledgementsThe authors wish to thank C. Genoud and E. Welker

(University of Lausanne) for providing EM illustrations and

J. Glowinski (Collge de France, Paris) for his support and

interest for our work.

Competing interests statementThe authors declare no competing financial interests.

DataBasesEntrez Gene:http://www.ncbi.nlm.nih.gov/geneOMIM:http://www.ncbi.nlm.nih.gov/omim

Alzheimers disease

UniProtKB:http://www.uniprot.org

Cx30|Cx43

suPPleMentarY inForMationSee online article:S1(table) | S2 (table)

All liNks Are AcTive iN The oNliNe pdf

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http://www.ncbi.nlm.nih.gov/genehttp://www.ncbi.nlm.nih.gov/omimhttp://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=104300http://www.uniprot.org/http://www.uniprot.org/http://www.uniprot.org/uniprot/O95452http://www.uniprot.org/uniprot/O95452http://www.uniprot.org/uniprot/P17302http://www.uniprot.org/uniprot/P17302http://www.nature.com/nrn/journal/v11/n2/suppinfo/nrn2757.htmlhttp://www.nature.com/nrn/journal/v11/n2/suppinfo/nrn2757.htmlhttp://www.nature.com/nrn/journal/v11/n2/suppinfo/nrn2757.htmlhttp://www.nature.com/nrn/journal/v11/n2/suppinfo/nrn2757.htmlhttp://www.nature.com/nrn/journal/v11/n2/suppinfo/nrn2757.htmlhttp://www.nature.com/nrn/journal/v11/n2/suppinfo/nrn2757.htmlhttp://www.uniprot.org/uniprot/P17302http://www.uniprot.org/uniprot/O95452http://www.uniprot.org/http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=104300http://www.ncbi.nlm.nih.gov/omimhttp://www.ncbi.nlm.nih.gov/gene

Astroglia Nature 2010

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Transcript of Astroglia Nature 2010