Glia: they make your memories stick!
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<ul><li><p>t2</p><p>tute77e</p><p>Review TRENDS in Neurosciences Vol.30 No.8structural and metabolic support. Effectively, they havebeen viewed as the brain glue that maintains neuronalintegrity.</p><p>There is now a growing body of evidence indicating thatglial cells, particularly astrocytes, contribute actively tosynapse development, synaptic transmission and neuronalexcitability . Collectively, these data have fuelled theemerging concept that the synapse is, in fact, a three-sidedor tripartite structure . In this tripartite synapse, astro-cytes are an integral component of the chemical synapse.According to this model, glial cells sense synaptic activity</p><p>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 . Althoughglycine itself can serve this purpose, recent work hasdemonstrated that another amino acid, D-serine, also bindsto this site with high affinity [8,18].</p><p>Corresponding author: Oliet, S.H.R. (email@example.com).Available online 12 July 2007.</p><p>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</p><p>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.</p><p>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 . 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</p><p>, University of Calgary, Calgary, Alberta, CanadaBordeaux, France</p><p>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+ , 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). 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.</p><p>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</p></li><li><p>of t</p><p>iii).</p><p>ded</p><p>is re</p><p>indin</p><p>tory</p><p>el), D</p><p>duc</p><p>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</p><p>Figure 1. D-serine is an endogenous ligand of NMDAR. (a) In the supraoptic nucleus</p><p>and does not co-localize with a neuronal marker, such as oxytocin (OT; red) (ii and</p><p>synaptic NMDA currents are strongly affected when D-serine is specifically degra</p><p>degraded by GO. Under conditions in which the astrocytic coverage of neurons</p><p>environment of neurons governs the level of occupancy of the NMDAR glycine-b</p><p>neurons is intact, addition of D-serine to the bathing solution has a small facilita</p><p>occupancy of the glycine-binding site is high. Conversely, in lactating rats (right pan</p><p>of occupancy of the glycine-binding site. These data fit with the idea that the re</p><p>concentration of D-serine in the synaptic cleft (Adapted from ).nervous system resembles that of NMDARs . Whereasdetailed analysis of its staining indicates that D-serine isenriched in astrocytic processes (Figure 1a) , 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.</p><p>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 .</p><p>www.sciencedirect.comWhereas most observations are consistent with thehypothesis that glial-derived D-serine is essential for</p><p>he rat hypothalamus, D-serine (green) is exclusively localized in the glial network (i)</p><p>(b) In virgin rats, where the glial coverage of supraoptic neurons is intact, evoked</p><p>by the enzyme DAAO, whereas they are unaffected when glycine is specifically</p><p>duced in lactating animals, NMDAR currents are strongly impaired. (c) The glial</p><p>g site by D-serine. In virgin rats, under conditions in which the glial coverage of</p><p>effect on the NMDAR-mediated current (left panel), indicating that the level of</p><p>-serine induced a strong increase in NMDAR currents, as expected from a low level</p><p>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 . 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 , which is accompaniedby a reduction in measured levels of hippocampal D-serine. In agreement with this observation, LTP in CA1 canbe rescued completely by supplying D-serine to the tissue. Taken together, these findings indicate that astrocyticD-serine regulates NMDAR-dependent synaptic plasticityat Schaffers 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.</p><p>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</p></li><li><p>undergo profound and reversible anatomical remodellingin different brain regions as a function of different phys-iological and/or pathological conditions . 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 neuronglia interactions that result fromchanges in glutamate clearance and diffusion [34,35]. Butit is the demonstration that D-serine, and not glycine, is the</p><p>control conditions now elicit LTD (Figure 2a). This isconsistent with reports on both the CA1  and CA3 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.</p><p>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 . These dataare consistent with the Bienenstock, Cooper and Munromodel of variation in the threshold for LTP induction ,which predicts that the relationship between synapticactivity and persistent changes in synaptic strength can</p><p>emb</p><p>are r</p><p>ed</p><p>. (b</p><p>(bla</p><p>nse</p><p>Review TRENDS in Neurosciences Vol.30 No.8 419endogenous 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 .</p><p>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. 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</p><p>Figure 2. D -serine-mediated metaplasticity. (a) Pairing synaptic stimulation with m</p><p>control). By contrast, in lactating animals, where D-serine levels in the synaptic cleft</p><p>supplying D-serine to the slices (right panel; D-serine), whereas LTP can be transform</p><p>The short bar represents the time during which the pairing protocol was applied</p><p>stimulation, according to the model described by Bienenstock, Cooper and Munro</p><p>causes a rightward shift of the activity dependence of synaptic plasticity. As a coImportantly, this relationship between plasticity and synaptic stimulation is governed by</p><p>environment (Adapted from ).</p><p>www.sciencedirect.comvary 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 anatomicalneuronglia remodelling might not be a common featureof all brain areas, it is tempting to speculate that modu-lation of...</p></li></ul>
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