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    Review TRENDS in Neurosciences Vol.30 No.8structural 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 [24]. 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

    ligand-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].

    Corresponding author: Oliet, S.H.R. (stephane.oliet@bordeaux.inserm.fr).Available online 12 July 2007.

    www.sciencedirect.com 0166-2236/$ see front matter 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2007.06.007Glia: they make youJaideep S. Bains1 and Stephane H.R. Olie1Department of Physiology & Biophysics, Hotchkiss Brain Insti2 Inserm Research Center U862, Institut Francois Magendie, 3303Universite Victor Segalen Bordeaux 2, 33077 Bordeaux, Franc

    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.

    Glianeuron 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, andr memories stick!,3

    , University of Calgary, Calgary, Alberta, CanadaBordeaux, France

    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 [3,4,68]. 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)[911]. 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 of

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    418 Review TRENDS in Neurosciences Vol.30 No.8D-Serine is present in significant amounts in the brain ofrodents and humans, and its distribution in the rat central

    Figure 1. D-serine is an endogenous ligand of NMDAR. (a) In the supraoptic nucleus

    and does not co-localize with a neuronal marker, such as oxytocin (OT; red) (ii and

    synaptic NMDA currents are strongly affected when D-serine is specifically degra

    degraded by GO. Under conditions in which the astrocytic coverage of neurons

    environment of neurons governs the level of occupancy of the NMDAR glycine-b

    neurons is intact, addition of D-serine to the bathing solution has a small facilita

    occupancy of the glycine-binding site is high. Conversely, in lactating rats (right pan

    of occupancy of the glycine-binding site. These data fit with the idea that the re

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

    www.sciencedirect.comWhereas most observations are consistent with thehypothesis that glial-derived D-serine is essential for

    he rat hypothalamus, D-serine (green) is exclusively localized in the glial network (i)

    (b) In virgin rats, where the glial coverage of supraoptic neurons is intact, evoked

    by the enzyme DAAO, whereas they are unaffected when glycine is specifically

    duced in lactating animals, NMDAR currents are strongly impaired. (c) The glial

    g site by D-serine. In virgin rats, under conditions in which the glial coverage of

    effect on the NMDAR-mediated current (left panel), indicating that the level of

    -serine induced a strong increase in NMDAR currents, as expected from a low level

    ed glial coverage of supraoptic neurons in lactating rats results in a diminishedNMDAR 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 supply