glia: they make your memories stick!

Glia: they make your memories stick!Jaideep S. Bains1 and Stephane H.R. Oliet2,3

1 Department of Physiology & Biophysics, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada2 Inserm Research Center U862, Institut Francois Magendie, 33077 Bordeaux, France3 Universite Victor Segalen Bordeaux 2, 33077 Bordeaux, France

Review TRENDS in Neurosciences Vol.30 No.8

Synaptic plasticity underlies higher brain functions suchas learning and memory. At glutamatergic synapses inthe vertebrate central nervous system, plasticity usuallyrequires changes in the number of postsynaptic AMPAreceptors. Recently, several studies have revealed thatglial cells play an important role in regulating postsyn-aptic AMPA receptor density. This is accomplishedthrough the release of gliotransmitters such as D-serine,ATP and TNF-a. More specifically, the availability ofD-serine, the endogenous co-agonist of N-methyl-D-aspartate receptors in many brain areas, governs theinduction of long-term potentiation and long-termdepression. Meanwhile, ATP and TNF-a trigger long-lasting increases in synaptic strength at glutamatergichypothalamic and hippocampal inputs, respectively,through mechanisms that promote AMPA receptorinsertion in the absence of coincident presynaptic andpostsynaptic activity. These data clearly demonstrate avital role for glia in plasticity and argue that their con-tributions to brain function extend well beyond theiroutdated role as cellular ‘glue’.

Glia–neuron communicationIn the nervous system, the chemical synapse formsthe functional unit for the transmission of informationbetween the nerve terminal and its target. The classicalpicture of a private, one-way dialogue is being re-evalu-ated on the strength of recent demonstrations indicatingthat glial cells, the presumed electrically silent co-habitants of the nervous system, might be a critical thirdelement of the synapse [1]. Hints of the interdependenceof this relationship can be gleaned from anatomicalobservations that astrocytic processes can enwrap up to60% of the neuronal synaptic structure. In spite of thisphysical intimacy, astrocytes have been thought to servefunctions primarily related to cellular housekeeping, andstructural and metabolic support. Effectively, they havebeen viewed as the brain ‘glue’ that maintains neuronalintegrity.

There is now a growing body of evidence indicating thatglial cells, particularly astrocytes, contribute actively tosynapse development, synaptic transmission and neuronalexcitability [2–4]. Collectively, these data have fuelled theemerging concept that the synapse is, in fact, a three-sidedor tripartite structure [1]. In this tripartite synapse, astro-cytes are an integral component of the chemical synapse.According to this model, glial cells sense synaptic activity

Corresponding author: Oliet, S.H.R. ([email protected]).Available online 12 July 2007.

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through a broad variety of ion channels, transporters andreceptors expressed on their surface. Depending on whichsynaptic inputs are activated and the glial receptorsinvolved, a host of intracellular second messenger path-ways, including Ca2+ [5], are activated. In turn, thisinduces the release of active substances from glial cells,termed gliotransmitters, which can act on both neighbour-ing glia and neurons. The ever-expanding list of knowngliotransmitters that mediate astrocyte to neuron signal-ling currently includes glutamate, taurine, ATP, D-serineand TNF-a [3,4,6–8]. This review will focus on recentstudies demonstrating that some of these gliotransmitters,D-serine, ATP and TNF-a in particular, can induce orcontrol persistent changes in synapse strength throughthe insertion or removal of AMPA receptors (AMPARs)[9–11]. This includes effects on N-methyl-D-aspartate re-ceptor (NMDAR)-dependent long-term potentiation (LTP)and long-term depression (LTD), as well as homeostaticand activity-independent plasticity. Here, we will reviewthe different mechanisms by which glial cells contribute tosynaptic plasticity at central synapses and provide somecontext for these intriguing new observations in terms ofour current understanding of brain signalling.

Glial-derived D-serine controls NMDAR-dependentactivity and plasticityIn the mammalian brain, activity-dependent persistentchanges in synaptic strength are believed to be essentialfor cognitive processes and higher functions, such as learn-ing and memory. NMDAR-dependent LTP and LTD arethe best-described forms of synaptic plasticity in the cen-tral nervous system [12,13]. A sufficiently robust rise inpostsynaptic Ca2+, associated with NMDAR activation,triggers a cascade of intracellular signalling events culmi-nating in either insertion (LTP) or removal (LTD) ofAMPARs at glutamatergic synapses [12,14]. In terms ofligand-gated channels, NMDARs possess two unique fea-tures. First, they exhibit an Mg2+-dependent block athyperpolarized potentials [15,16]. This block is relievedby membrane depolarization, meaning that NMDARseffectively serve as coincidence detectors for presynapticand postsynaptic activity and thus are ideal candidatesfor mediators of synapse-specific activity-dependentplasticity. Second, in addition to glutamate, their acti-vation requires the binding of a second agonist, glycine,to a strychnine-insensitive binding site [17]. Althoughglycine itself can serve this purpose, recent work hasdemonstrated that another amino acid, D-serine, also bindsto this site with high affinity [8,18].

d. doi:10.1016/j.tins.2007.06.007

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Figure 1. D-serine is an endogenous ligand of NMDAR. (a) In the supraoptic nucleus of the rat hypothalamus, D-serine (green) is exclusively localized in the glial network (i)

and does not co-localize with a neuronal marker, such as oxytocin (OT; red) (ii and iii). (b) In virgin rats, where the glial coverage of supraoptic neurons is intact, evoked

synaptic NMDA currents are strongly affected when D-serine is specifically degraded by the enzyme DAAO, whereas they are unaffected when glycine is specifically

degraded by GO. Under conditions in which the astrocytic coverage of neurons is reduced in lactating animals, NMDAR currents are strongly impaired. (c) The glial

environment of neurons governs the level of occupancy of the NMDAR glycine-binding site by D-serine. In virgin rats, under conditions in which the glial coverage of

neurons is intact, addition of D-serine to the bathing solution has a small facilitatory effect on the NMDAR-mediated current (left panel), indicating that the level of

occupancy of the glycine-binding site is high. Conversely, in lactating rats (right panel), D-serine induced a strong increase in NMDAR currents, as expected from a low level

of occupancy of the glycine-binding site. These data fit with the idea that the reduced glial coverage of supraoptic neurons in lactating rats results in a diminished

concentration of D-serine in the synaptic cleft (Adapted from [11]).

418 Review TRENDS in Neurosciences Vol.30 No.8

D-Serine is present in significant amounts in the brain ofrodents and humans, and its distribution in the rat centralnervous system resembles that of NMDARs [19]. Whereasdetailed analysis of its staining indicates that D-serine isenriched in astrocytic processes (Figure 1a) [20], someimmunoreactivity has also been described in neurons ofthe cerebral cortex, the brainstem, the hippocampus andthe olfactory bulb [21,22]. Whether the presence ofneuronal D-serine reflects a synthesis activity or an uptakeprocess, and whether it can be released in the extracellularspace to regulate NMDAR function remains to be deter-mined. It is worth mentioning that earlier experimentscarried out in hippocampal cultures showed that the regu-lation of NMDARs by endogenous D-serine occurred onlywhen neurons and glia were co-cultured but not in pureneuronal cultures [23,24], arguing against a role forneuronal D-serine in controlling NMDAR activity.

The functional consequences of D-serine binding toNMDARs have been investigated using D-amino acidoxidase (DAAO), an enzyme that specifically degradesD-serine. In the hippocampus, the retina and the hypo-thalamus, DAAO considerably reduced NMDAR-mediatedcurrents [23,24] (Figure 1b). Because DAAO does not affectglycine levels, this provides strong evidence that endogen-ous D-serine is required for NMDAR activity in thesestructures. This assertion was confirmed in the supraopticnucleus of the rat hypothalamus; specifically degradingglycine with glycine oxidase (GO) did not affect NMDAR-mediated currents [23,24]. That D-serine is themajor, if notonly, endogenous co-agonist of NMDARs is a conclusionthat was also drawn from studying NMDAR-mediatedneurotoxicity in the hippocampus [25].

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Whereas most observations are consistent with thehypothesis that glial-derived D-serine is essential forNMDAR activity, they do not address whether it is necess-ary for the induction of LTP and LTD. This question wasanswered by experiments in hippocampal cell cultures andbrain slices demonstrating that reducing D-serine levelsusing DAAO dramatically compromised the induction ofLTP in response to high-frequency stimulation, whereassupplementing the media with saturating concentrationsof exogenous D-serine restored LTP [24]. Additional evi-dence supporting the involvement of D-serine in synapticplasticity can be gleaned from the study of senescence-accelerated mice. These animals exhibit a significantdeficit in hippocampal LTP [26], which is accompaniedby a reduction in measured levels of hippocampal D-serine[27]. In agreement with this observation, LTP in CA1 canbe rescued completely by supplying D-serine to the tissue[26]. Taken together, these findings indicate that astrocyticD-serine regulates NMDAR-dependent synaptic plasticityat Schaffer’s collaterals. Whether this applies to othercentral synapses remains to be further investigated. If thiswere the case, glial cells would be key protagonists inall physiological and pathological processes involvingNMDARs.

The glial environment governs NMDAR-dependentsynaptic plasticityBecause most D-serine is synthesized by and released fromastrocytes, its ability to affect neuronal function willdepend on the physical relationship between astrocyticand neuronal elements. It is now accepted that the cover-age of neurons by glial cells is extremely dynamic. It can

Review TRENDS in Neurosciences Vol.30 No.8 419

undergo profound and reversible anatomical remodellingin different brain regions as a function of different phys-iological and/or pathological conditions [28–32]. In thehypothalamo-neurohypophysial system (HNS), such ana-tomical plasticity can be observed during different phys-iological conditions, such as lactation, parturition andchronic dehydration [32,33]. This system consists of mag-nocellular neurosecretory neurons located in the hypo-thalamic supraoptic and paraventricular nuclei, whoseaxons project to the neurohypophysis. Here, their hormonecontent, namely oxytocin and vasopressin, is released intothe general circulation. The morphological plasticity ofthe HNS is characterized by a pronounced reduction inastrocytic coverage of oxytocin-secreting magnocellularneurons, which is entirely reversible upon the cessationof the stimulation. This remodelling has significant con-sequences for neuron–glia interactions that result fromchanges in glutamate clearance and diffusion [34,35]. Butit is the demonstration that D-serine, and not glycine, is theendogenous co-agonist of NMDARs in the HNS (Figure 1b)that makes this a particularly useful model to study thephysiological impact of glial-derived D-serine within thecontext of glutamatergic transmission and NMDAR-de-pendent synaptic plasticity [11].

Most interestingly,whenastrocytic coverage of neuronsis diminished, NMDAR-mediated synaptic responses aredecreased, consistent with the idea that a gliotransmitteris involved. These responses can be recovered when themedia is supplemented with saturating concentrations ofD-serine (Figure 1c), providing the final evidence thatglial-derived D-serine is the endogenous ligand ofNMDARs in the HNS. Under conditions in which D-serineconcentrations within the synaptic cleft are reduced, thenumber of NMDARs available for synaptic activation isalso reduced, resulting in dramatic changes in the induc-tion of activity-dependent plasticity such as LTP and LTD[11]. Conditions of reduced astrocyte coverage are associ-ated with a shift in the activity dependence of long-termsynaptic changes towards higher activity values. Simplyput, experimental protocols that caused LTP under

Figure 2. D -serine-mediated metaplasticity. (a) Pairing synaptic stimulation with memb

control). By contrast, in lactating animals, where D-serine levels in the synaptic cleft are r

supplying D-serine to the slices (right panel; D-serine), whereas LTP can be transformed

The short bar represents the time during which the pairing protocol was applied. (b

stimulation, according to the model described by Bienenstock, Cooper and Munro (bla

causes a rightward shift of the activity dependence of synaptic plasticity. As a conse

Importantly, this relationship between plasticity and synaptic stimulation is governed by

environment (Adapted from [11]).


control conditions now elicit LTD (Figure 2a). This isconsistent with reports on both the CA1 [36] and CA3[37] regions of the hippocampus that demonstrate a switchto LTD when high-frequency stimulation is applied in thepresence of partial NMDAR blockade. The most parsimo-nious explanation for this switch in the direction ofplasticity is that a reduction in the number of NMDARsrecruited during the induction protocol translates intoa smaller postsynaptic increase in Ca2+. This is no longersufficient to trigger LTP, but is appropriate for themanifestation of LTD.

In hypothalamic slices from lactating rats, applicationof saturating concentrations of D-serine increased the num-ber of NMDARs available for activation in this situation,thereby entirely rescuingNMDARactivity [11]. These dataare consistent with the Bienenstock, Cooper and Munromodel of variation in the threshold for LTP induction [38],which predicts that the relationship between synapticactivity and persistent changes in synaptic strength canvary according to the number of NMDARs available duringsynaptic activation (Figure 2b). Effectively, by adjustingthe D-serine occupancy of the NMDAR glycine-binding site,astrocytes can shift the relationship between activity andsynaptic strength. That endogenous D-serine is the co-agonist of NMDARs at some central synapses could be ofprime importance under physiological and/or pathologicalconditions in which the anatomical interaction betweenneurons and glia is modified. Although anatomicalneuron–glia remodelling might not be a common featureof all brain areas, it is tempting to speculate that modu-lation of D-serine release from glial cells, for instancethrough synaptic activation of glutamatergic receptorslocated on astrocytes [23], would affect the concentrationof the D-amino acid within the synaptic cleft and con-sequently the number of NMDARs available for activation,thereby modifying the activity dependence of long-termsynaptic plasticity. By governing NMDAR activationthrough D-serine release, glial cells are ideally suitedto modulate NMDAR-dependent functions, includingpersistent changes in synaptic strength.

rane depolarization induces LTP in the supraoptic nucleus of virgin rats (left panel;

educed, it causes LTD (right panel; control). LTP can be restored in lactating rats by

into LTD in virgin animals when D-serine is degraded with DAAO (left panel; DAAO).

) At these synapses, the induction of plasticity depends on the rate of synaptic

ck curve; virgin). Glial withdrawal in the supraoptic nucleus (red curve; lactating)

quence, an LTP-inducing protocol in virgin animals causes LTD in lactating rats.

the availability of D-serine in the synaptic cleft, which is itself dependent on the glial


Gliotransmitters and synaptic scalingIn addition to contributing to classical Hebbian forms ofplasticity, recent studies have provided evidence that thegliotransmitters TNF-a [9,39,40] and ATP [10] increasesynaptic strength at glutamatergic synapses independentof coincident changes in presynaptic and postsynapticactivity. The acute application of TNF-a increases thesurface expression of synaptic AMPARs at hippocampalsynapses [9,40], whereas ATP increases AMPAR insertionat hypothalamic synapses [10]. Although an increase insurface expression of AMPARs is also observed followingNMDAR-dependent LTP [14], there are important differ-ences between these processes. First, there is no synapsespecificity in response to TNF-a or ATP. Second, and in linewith the first observation, there is no requirement forcoincident presynaptic and postsynaptic activity. Thisobservation opens up new possibilities with regards tohow synaptic strength is controlled and also raises newquestions about the mechanisms by which these newplayers achieve the same end point — namely an increasein the number of AMPARs on the postsynaptic membrane.Here, we will discuss these observations and examine themechanisms by which they promote AMPAR insertion.

TNF-a and AMPAR insertion

It is clear that the increase in AMPAR expression by TNF-a requires obligatory activation of TNF-1 receptors [9].These receptors are remarkably promiscuous, activatinga plethora of intracellular signalling cascades [41]. Theincrease in surface expression of AMPARs depends on theactivation of phosphatidyl inositol 3-kinase (PI3-kinase)[40], which is also recruited during AMPAR insertionfollowing LTP [42–44]. Although TNF-a can also bereleased by neurons, the observation that the increase inAMPAR surface expression when neuronal cultures areexposed to astrocyte-conditioned media can be blocked byTNF-1 receptor inhibitors argues strongly in favour of aglial source [9]. Interestingly, the removal of TNF-a frombrain slices results in a weakening of synapses [9],suggesting that this gliotransmitter is important not onlyin increasing synaptic strength, but also in maintaining or‘preserving’ it. This is consistent with previous workarguing for an obligatory role for glia in the formation offunctional glutamate synapses in neuronal networks [45].The current observations extend these ideas and raise thepossibility that glia might participate in synaptic com-munication in an ongoing fashion, sensing changes insynaptic activity and effectively altering the synaptic can-vas for activity-dependent changes in the adult nervoussystem.

Interestingly, although TNF-a strengthens glutamater-gic synapses, it has no impact on the ability of synapses toundergo rapid activity-dependent LTP or LTD [39].Rather, it appears to play a critical role in the expressionof some forms of homeostatic plasticity [39]. Unlike LTP orLTD, homeostatic plasticity refers to a change in thestrength of synapses that occurs in response to chronicincreases or decreases in neuronal activity [46]. In prin-ciple, a persistent (hours to days) decrease in neuronalactivity causes a compensatory increase in the expressionof AMPARs — effectively an attempt by the neuron to


increase excitatory input when faced with a prolongedquiescent period [46–48]. Conversely, an increase inactivity is met by an effort to ‘turn down the volume’ bydecreasing the number of AMPARs. It now appears thatsome elements of homeostatic plasticity might depend onTNF-a signalling from glia [39], because the increase inAMPAR expression in response to chronic activity block-ade in neuronal cultures can be blocked either by antag-onizing the actions of TNF-a or by repeating the aboveexperiments in TNF�/� mice.

A similar role has been reported previously for brain-derived neurotrophic factor (BDNF) with regards to glu-tamate receptors on interneurons, but not pyramidal cells[49]. Are these observations indicative of a dichotomybetween the mechanisms that drive AMPAR insertion ininterneurons and pyramidal cells, or do they indicate thathomeostatic plasticity is regulated differently at hippo-campal neurons [39] compared to cortical neurons [49]?Experiments on interneurons from the hippocampuswouldbe one way to begin to address this intriguing issue. Thesefindings are extremely thought-provoking, but severalimportant questions remain. For example, it is not clearexactly how glia would sense changes in activity and thenincrease or decrease TNF-a release accordingly. Althoughthere is some evidence that glutamate might be the signalthat is sensed by glia [39], this issue is far from resolved. Inaddition, there might be subtle differences in the acuteeffects of TNF-a in comparison to its long-term effects.Acute application of TNF-a increases the frequency ofAMPA-mediated quantal currents [9,40]. By contrast,the effects of TNF-a associated with chronic activity block-ade result in an increase in the amplitude of quantalcurrents [39]. Perhaps there is an immediate effect ofTNF-a in which silent synapses are made functional(responsible for the increase in frequency), followed byadditional insertion at all synapses (hence the increasein amplitude). This scenario, however, seems unlikely, asthe increase in frequency does not persist following chronicactivity blockade [39]. An alternative scenario might bethat there is an initial period when silent synapses becomefunctional. Then, during the 24-hour period of activityblockade, some synapses are functionally pruned whilethe ones that remain are strengthened through additionalAMPAR insertion. This local form of scaling might dependon the rate at which quanta are released at individualsynapses and might promote synaptic stabilization [50].Furthermore, it is not known whether TNF-a-inducedhomeostatic plasticity is observed uniformly at allsynapses. If synaptic weights are to be maintained, thenthere should be multiplicative scaling [48] at all synapsesin response to TNF-a. Finally, as noted previously,whereas homeostatic plasticity is a bi-directional process[46], the involvement of TNF-a appears to be limited tocompensatory changes resulting from chronic activityblockade and it appears that TNF-a does not participatein controlling the AMPAR numbers observed followingchronic activity elevations. These observations indicate aclear need for additional efforts to further parse outthe potentially bourgeoning role of gliotransmitters inthis very interesting and complex form of synapticplasticity.


ATP and AMPAR insertion

Recent work indicates that, at synapses in the paraven-tricular nucleus of the hypothalamus, glial-derived ATPcontributes to long-term changes in synaptic strengththrough its actions at postsynaptic P2X7 receptors [10].When released into the extracellular space, ATP can bebroken down quickly into another well-known chemicalsignal, adenosine, which is important in mediating hetero-synaptic depression in the hippocampus [51–53]. Thisconversion, however, occurs in a regulated fashion throughthe action of ectonucleotidases [54], which can be expressedto varying degrees in different brain regions and even indifferent subfields of the same structure [55]. If ATP is notconverted to adenosine, it is free to act on a host ofpurinergic receptors, including both the ionotropic P2Xreceptors and the metabotropic P2Y receptors. Both re-ceptor families have been implicated in ATP-mediatedshort-term synaptic plasticity, but recent biochemical evi-dence indicating that some P2X receptors, in particularP2X7, can directly activate PI3-kinase, a key mediator ofAMPAR insertion [42,43], has led to speculation that thesereceptors might also contribute to changes in synapticstrength [56]. In addition, P2X7 receptors are Ca2+ per-meable [57] (like NMDARs), but, unlike NMDARs, they donot exhibit any voltage-dependent block [57]. Thus, theyprovide an interesting target through which plasticitycould be induced at synapses in a manner that does notrequire coincident activity.

Much like the reports on TNF-a discussed above, theactions of ATP are not dependent on coincident presynaptic

Figure 3. Glial-derived ATP induces AMPAR insertion in the hypothalamus. (a) In contr

the amplitude of miniature synaptic currents. This effect is blocked when the slice is

obligatory role for ATP signalling. (b) Following dehydration, glial processes retract f

synaptic current amplitude. Importantly, application of the P2X7 agonist BzATP robustl

not compromised (adapted from [10]).


and postsynaptic activity, and also appear to promote theinsertion of AMPARs into the synapse. This latter pointwas driven home by experiments showing that disruptionof several intracellular signals that are critical to AMPARinsertion, such as an increase in intracellular Ca2+ [13], theactivation of PI3-kinase [42,43] and the SNARE-dependentexocytosis of vesicles with the postsynaptic membrane [14],blocks the ATP-mediated increase in synaptic strength[10]. Although ATP could be released by neurons[58–60], it appears that, in the current study, the primarysource is glial. This is based on several observations, in-cluding the demonstration that neuron-free glial culturesrelease ATP when stimulated by noradrenaline (NA).Additionally, the effects of NA were blocked when exper-imentswere conducted in slices prepared from rats inwhichthe astrocytic coverage of hypothalamic synapses hadundergone remodelling following dehydration [25](Figure 3). A similar attenuation was observed when gliawere metabolically inhibited by fluorocitric acid [61], amanipulation that also decreases NA-stimulated ATPrelease from glial cultures. Although these observationsestablish a clear role for glial cells and ATP, they do notnecessarily implicate a particular purinergic receptor in theprocess. This was established first by demonstrating thatthe amplitude ofminiature excitatory postsynaptic currents(mEPSCs) was increased by micromolar doses of BzATP, anon-hydrolysable form of ATP that exhibits preferentialbinding (in comparison to ATP) to P2X7 receptors. Further-more, blocking P2X7 receptors with brilliant blue G (BBG)completely blocked the effects of NA on synaptic strength.

ol conditions, when glial processes are closely apposed to synapses, NA increases

incubated with BBG, an antagonist of the purinergic P2X7 receptor, indicating an

rom the synapse and, under these conditions, NA fails to increase the miniature

y increases current amplitude, indicating that postsynaptic purinergic signalling is

Figure 4. Contributions of glial cells to synaptic plasticity in the brain. This schematic depicts the effects of three different gliotransmitters on synaptic strength. On the left,

TNF-a and ATP promote AMPAR insertion. In both cases, this requires the postsynaptic activation of PI3-kinase. TNF-a binds to TNF-1 receptors, whereas ATP binds to Ca2+-

permeable P2X7 receptors. On the right, glia can also release D-serine, which binds to the glycine-binding site of postsynaptic NMDARs and thereby alters the activity

dependence of Hebbian forms of synaptic plasticity.


Interestingly, there appears to be some specificityregarding the signals that release gliotransmitters, asother manipulations that have been shown to increaseintraglial Ca2+, such as the presence of baclofen or highK+, failed to elicit changes in synaptic strength [10]. It isnot clear yet whether the activation of other Gq-coupledreceptors, such as group I metabotropic glutamate recep-tors, would also be suitable triggers of ATP release, butthese findings do raise interesting questions about how therelease of gliotransmitters can be regulated in such adiscriminating fashion and open new possibilities forlinking specific extracellular signals to specific, perhapsspatially segregated, release pathways in glia. TheATP-mediated increase in synaptic strength appears toshare many of the mechanisms described for LTP andhomeostatic scaling — namely a Ca2+-dependent vesicularfusion event that inserts AMPARs into the postsynapticmembrane — but is unique in that it does not requireeither NMDAR activation or persistent changes in post-synaptic activity before induction. These findings alsoindicate the need for additional experiments, includingclarifying the specific mechanisms by which ATP isreleased in response to various stimuli and determiningthe conditions that enable ATP to be effectively ‘protected’from breakdown by extracellular ectonucleotidases. Onepossibility is that this bi-directional switch from ATP toadenosinemight be controlled by small regional changes inthe extracellular pH [62], which could determine whetherthe glial release of ATP increases or decreases synapticstrength. Collectively, these findings argue that glial ATPacts on postsynaptic neurons to increase the insertion ofAMPARs.


SummaryIt is now clear that gliotransmitters play essential roles inthe mammalian brain [3,4]. They not only transientlymodulate synaptic transmission and neuronal excitability,but also are responsible for persistent changes in synapsestrength. Whereas glial cells govern NMDAR-dependentsynaptic plasticity through the release of D-serine in differ-ent brain regions, the gliotransmitters TNF-a and ATP areresponsible for inducing NMDAR-independent forms ofLTP in the hippocampus and the hypothalamus, respect-ively. Taken together, these data indicate that glia con-tribute actively to the transfer and storage of informationin the central nervous system (Figure 4). In addition, asglial cell processes can also form physical communicationpoints with adjacent glia, resulting in a lattice of inter-connected cells capable of propagating short- and long-range signals [63], these observations raise the possibilitythat the glial influence might extend to discrete spatial‘domains’. The findings reviewed above, however, are onlybeginning to scratch the surface of what will be anexplosion of findings related to glial modulation of brainfunction [64]. For example, we did not touch on the richnessof glial cell diversity, including exciting new informationabout signalling between neurons and oligodendrocyteprecursor cells [65,66], or on the potential interactionsamong the different glial cell types. In this regard,the recent observation that the release of ATP from astro-cytes can recruit microglia, which, in turn, release BDNFto alter the expression of a transmembrane K+-Cl� co-transporter in the spinal cord [67], begins to highlightthe potential interdependence and complexity of theseinteractions.


Finally, the findings described above indicate that glialcells might become prime targets in pathological eventsthat are associated with a deficit in synaptic plasticity,including stroke, epilepsy, peripheral neuropathies, Par-kinson’s, Alzheimer’s and Huntington’s diseases, andschizophrenia. Whereas previous therapeutic approachescentred directly on neurons have been associated withdeleterious side effects, the emergence of glial cells asactive protagonists in these processes now provides theopportunity for new strategies for the development ofdrugs that would target synaptic function indirectlythrough the modulation of gliotransmitter metabolismand release.

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67 Coull, J.A. et al. (2005) BDNF from microglia causes the shift inneuronal anion gradient underlying neuropathic pain. Nature 438,1017–1021

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