d -Serine signalling in the brain: friend and foe

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D-Serine

signalling in the brain: friend and foe

Magalie Martineau1, Ge´rard Baux2 and Jean-Pierre Mothet1 1

Laboratoire de Neurobiologie Morphofonctionnelle, INSERM U378, 146 Rue Le´o Saignat, 33077 Bordeaux, France Institut de Neurobiologie Alfred Fessard, Laboratoire de Neurobiologie Cellulaire et Mole´culaire, CNRS UPR 9040, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette, France

2

Neurons and glia talk to each other at synapses. Glia sense the level of synaptic activity and consequently regulate its efficacy via the release of neuromodulators. One such glia-derived modulator is D-serine, an amino acid that serves as an endogenous ligand for the strychnine-insensitive glycine-binding site of NMDA glutamate receptors. Here, we provide an overview of recent findings on the mechanisms of its synthesis, release and clearance at synapses, with an emphasis on the dichotomy of behaviour of this novel messenger in the brain. The discovery of the good and ugly faces of this gliotransmitter is an important issue of modern neuroscience that has repercussions for the treatment of brain disorders. Introduction Classically, chemical synapses are viewed as polarized elements, and neurotransmitters are seen as neuronderived substances that are released upon depolarization of the nerve terminal and bind to specific receptors on the postsynaptic target cell. However, the CNS is made up of neurons and glia, with glia being by far the more numerous. In an ascending phylogenic scale, the numeric preponderance of glia over neurons is already notable in rodents, greatly increases in primates and reaches its peak in humans with a 4:1 ratio [1]. Glia are well positioned to communicate with neurons at synapses, where chemical communication occurs via their fine processes that are in close proximity to synapses [2]. Over the past decade, it has become evident that this intimate structural relationship is the locus of bidirectional communication between neurons and glia [3,4]. Thus, the emerging concept of the tripartite synapse considers astrocytes as dynamic partners of neurons at synapses, controlling synaptogenesis [5] and synaptic transmission [6]. Astrocytes are thought to control these processes by sensing the level of synaptic activity and, in turn, influencing synaptic activity by the regulated release of neuromodulators [3,4]. Although glutamate and ATP are the most well known ‘gliotransmitters’ mediating this astrocyte–neuron crosstalk, it is now obvious that D-serine, another amino acid, can be added to the list [7]. The discovery of D-serine in the CNS revolutionised our thinking and forced us to reconsider the long cherished dogma that only L-isomers of amino acids occur in mammalian tissues and body fluids. The present review Corresponding author: Mothet, J-P. ([email protected]). Available online 30 June 2006 www.sciencedirect.com

highlights the most recent findings about the molecular mechanisms controlling D-serine availability in the brain, which have led to the discovery that this atypical messenger not only has a vital role in promoting neuronal migration and synaptic plasticity but also behaves as a pro-death signal during excitotoxic and neuroinflammatory insults. How does the CNS make and degrade D-serine? Little attention was paid to D-serine function in the CNS until the identification of the glial pyridoxal 50 -phosphate (PLP)-dependent serine racemase (SR) [8]. This enzyme directly converts L-serine into D-serine, L-serine being the only source for endogenous D-serine in the brain. SR also converts D-serine into L-serine, albeit with lower affinity. Different genes for SR have been identified in mice, rats and humans [9–11] (Figure 1a). The distribution of SR is very similar to that reported for endogenous D-serine, with the highest expression in the forebrain [9,12]. In the CNS, SR is expressed mostly by glial fibrillary acidic protein (GFAP)-positive astrocytes [9,12,13] (Figure 1b), with some expression by quiescent and activated microglia [13,14]; in the peripheral nervous system SR is expressed by Schwann cells [15]. These observations could leave us with the idea that SR and then D-serine are strict markers of glia and that they never occur in neurons. But this is not the case. A more liberal model is needed because SR and Dserine have been found in some neurons of the cerebral cortex [13,16] and in hindbrain glutamatergic neurons [13]. Thus, neurons constitute a source for D-serine that, although much smaller than the glial one, is not negligible. In addition to PLP, SR activity is regulated in many different ways by different cellular compounds. Mg2+ and ATP are the most prevalent physiological cofactors of the enzyme that increase the rate of D-serine synthesis [17– 19]. In the presence of Mg2+, ATP half-maximally activates SR at 10 mM, which is far below the millimolar range of ATP levels found in astrocytes. Ca2+ might also represent another important SR cofactor because it binds to the enzyme, and production of D-serine is positively influenced by increases in intracellular Ca2+ concentrations in astrocytes [20]. By contrast, glycine and a series of metabolites related to L-aspartic acid (L-aspartic acid, L-asparagine and a,b-threo-3-hydroxyaspartic acid) competitively inhibit the enzyme [21,22] (Figure 1c). Because glycine concentrations in astrocytes are
3–6 mM, glycine would constitutively inhibit SR activity, unless glycine and SR show different compartmentalization within the astrocyte cytosol [22].

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Figure 1. D-Serine cycling and energy metabolism in astrocytes. (a) All genes for serine racemase (SR) comprise seven exons (red), the first exon containing the lysine residue (Lys56) that forms an internal Schiff base and the pyridoxal 50 -phosphate (PLP)-binding region [9–11]. Human and mouse SR genes respectively encode 340 and 339 amino acid proteins, whereas the rat SR has a truncated C-terminal sequence of six residues relative to the human SR. The three proteins share 89% identity in their amino acid sequence and all contain the consensus sequence ELFQKTGSFKIRGA for PLP binding at the N terminus [9–11]. Mutation of Lys56 inside this sequence abolishes racemization of L-serine into D-serine [9,23]. In agreement with the presence of alternative exons in the SR gene, different transcripts encode SR proteins of different sizes in the brain and other organs, indicating that different splice forms are dominant in different tissues [12]. Gene structures were retrieved from NCBI using the SNP gene view. Blue lines and blue boxes represent the 50 - and 30 -untranslated regions of the SR genes. (b) Double staining of the primate hippocampus for SR (red) and the astrocytic marker glial fibrillary acidic protein (GFAP, green) shows that the enzyme is expressed only in astrocytes. Regions of colocalization appear yellow in the overlay panel. Nuclei were visualized using 40 ,6-diamidino-2-phenylindole (DAPI, blue). Modified, with permission, from Ref. [12]. (c) In astrocytes, SR converts L-serine into D-serine. LSerine can originate from the diet, or from glial glycolysis through the glucose-3-phosphoglycerate-3-phosphoserine biosynthesis pathway or from glycine through the hydroxymethyltransferase pathway. In addition to its racemase activity, SR catalyzes the a,b-elimination of water from both L-serine and D-serine to form pyruvate. Then, SR-derived pyruvate can be shuttled to the mitochondrial tricarboxylic acid (TCA) cycle, where it is decarboxylated to give intermediates in the production of diverse amino acids (e.g. GABA, glutamate and glycine) and ATP; ATP in turn stimulates the a,b-elimination and racemization of D-serine. SR-derived pyruvate can also be converted by lactate dehydrogenase into lactate, thus providing energy for neurons. Furthermore, SR-derived pyruvate can be used by pyruvate carboxylase, a specific glial enzyme, to form aspartate. Both glycine and aspartate can in turn inhibit SR [21]. D-Serine can also be deaminated by D-amino acid oxidase (DAAO) to produce pyruvate, which can be used in all the pathways described for SR-derived pyruvate.

SR activity is also controlled by protein–protein interactions. Yeast two-hybrid screens have revealed that SR binds to glutamate-receptor-interacting protein (GRIP), a scaffolding protein for AMPA receptors. GRIP contains six PDZ domains, a motif associated with protein–protein interactions. SR binds selectively to PDZ-6 through the extreme part of its C-terminal portion that contains the PDZ-binding consensus sequence VSV. Mutation to glycine of the C-terminal valine residue of SR abolishes interactions with GRIP. Viral infection of cells with GRIP elicits a fivefold increase in the production of D-serine [23]. The physiological relevance of the GRIP–SR interactions is further supported by the fact that activation of AMPA receptors elicits a strong increase in SR activity [23]. It is proposed that activation of AMPA receptors leads to phosphorylation of the receptor, causing dissociation of GRIP that finally binds to SR (Figure 2). The relationship between SR and AMPA receptors raises an intriguing www.sciencedirect.com

issue. AMPA receptor currents are a predominant feature of GFAP-positive astrocytes and oligodendrocytes that display large outward-rectifying currents and no or poor glutamate transport, and they are absent in glia that exhibit variably-rectifying currents [24]. This difference might reflect different physiological functions because only glia with variably-rectifying currents are capable of fast uptake of extracellular K+ [24]. Furthermore, in the hippocampus, astrocytes that have different current profiles are anatomically segregated [24]. Thus, SR expression might be restricted to a subset of ‘non-passive’ astrocytes expressing AMPA receptors. Nevertheless, there is no evidence for such coexpression of SR and AMPA receptors in situ and this issue requires further investigation. Recently, Fujii and colleagues [25] have identified protein interacting with C-kinase (PICK1) as another protein that interacts with SR. Again, the binding of PICK1 to SR requires the PDZ domain of PICK1 and the C terminus

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Figure 2. D-Serine: a gliotransmitter in the core of glutamatergic synapses. Upon depolarization of nerve terminals (1), glutamate (large blue dots) is released into the synaptic space where it activates non-NMDA receptors (NMDARs) (2) on the membrane of perisynaptic astrocytes. This activation leads to influx of Ca2+ (small red dots) either through AMPA/kainate receptors or the reverse mode of the Ca2+–Na+ exchanger (not shown), and to release of Ca2+ from the endoplasmic reticulum (ER) in case of metabotropic glutamate receptors (3). Activation of AMPA receptors triggers their phosphorylation by protein kinase C (PKC) bound to protein interacting with C-kinase (PICK1), and causes dissociation of the scaffolding glutamate-receptor-interacting protein (GRIP) from the receptor. Subsequently, GRIP associates with and activates serine racemase (SR) [23]. PICK1 can also bind the enzyme or bring PKC close to SR, leading to phosphorylation of SR [25]. How GRIP and PICK1 interact to regulate SR remains unclear. Nevertheless, the coexpression of GRIP with SR causes a large increase in synthesis of D-serine (white triangles) [23]. D-Serine is consequently released, either from a cytosolic pool by a transporter (T) [38] or from a vesicular pool by a Ca2+-dependent and SNARE-dependent mechanism (4) [35]. Once in the synaptic cleft, D-serine, in concert with glutamate, activates NMDA receptors at the membrane of postsynaptic neuron, leading to the opening of ion channels (5). NMDA receptors bind to the postsynaptic density protein PSD95, which in turn binds to neuronal nitric oxide synthase (NOS). Ca2+ entry through NMDA receptors activates NOS by a Ca2+/calmodulindependent mechanism. Nitric oxide (NO) produced by NOS can diffuse to neighbouring cells, where it inhibits SR through nitrosylation and activates DAAO [31,32], which reduces D-serine levels. Clearance of D-serine from the synaptic space is assured by Na+-dependent and Na+-independent transporters (T) on the membrane of astrocytes and neurons (6). Although glia-derived D-serine predominates, neurons that also express SR release the amino acid upon activation of glutamate receptors, notably NMDA receptors [16]. D-Serine is released from neurons by a non-vesicular mechanism that involves an unidentified channel or transporter. Dotted lines represent putative pathways.

of SR. Mutation of a lysil–aspartate dipeptide within the PDZ domain of PICK1 abolishes the binding to SR, and mutation of SR by adding a tyrosine residue to the C terminus, to obscure the C-terminal valine residue, also abolishes the interactions of the two proteins [25]. In contrast to GRIP, the role of PICK1 in regulating SR is not established. Fujii and colleagues have proposed that PICK1 might escort protein kinase C to its target SR, resulting in phosphorylation of the enzyme (Figure 2). An intriguing feature of SR is that it catalyzes not only the production of D-serine but also that of pyruvate and ammonia, via the a,b-elimination of water from L-serine [17–19,26]. a,b-Elimination activity towards L-serine is higher than the racemization activity, resulting in the synthesis of three molecules of pyruvate per molecule of D-serine obtained through racemization [19,22,26]. The a,b-elimination and racemization of L-serine might be regulated differently; for example, ATP complexed to Mg2+ preferentially stimulates the a,b-elimination [19]. Perhaps SR switches between forming D-serine and forming pyruvate depending on the energy status of the cell. In glia, D-serine production is linked to the energy metabolism www.sciencedirect.com

pathway and to the metabolism of other amino acids (Figure 1c). Finally, SR-derived pyruvate is a potential source of lactate for neurons, providing energy during periods of enhanced synaptic activity or neuroprotection against oxidative damage and Zn2+ neurotoxicity [19]. Brain D-serine exhibits a half-life of
16 h [19] but the metabolic pathway responsible for its degradation remains elusive. Mammalian D-serine can be metabolized by the peroxisomal flavoprotein D-amino acid oxidase (DAAO), an enzyme present in astrocytes (Figure 1c) of the hindbrain and cerebellum [27–29]. Adult DAAO-deficient mice display increased D-serine levels, especially in areas where its levels are normally low [30]. Furthermore, D-serine levels are inversely related to the regional expression of DAAO during development [27–30]. However, DAAO levels are almost undetectable in D-serine-rich forebrain, and in DAAO-deficient mice D-serine levels appear relatively unchanged in this region [30]. Thus, other mechanisms probably regulate D-serine concentrations in this brain area. Indeed, SR also catalyzes a,b-elimination of water from D-serine [19,22]. Although a,b-elimination from D-serine is less effective than that from L-serine, astrocytes

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might physiologically regulate their content of D-serine in this way [19]. This novel function of SR represents an alternative mechanism for enzymatic removal of D-serine in regions of the brain where DAAO is absent. Notably, two recent studies provide some evidence that DAAO and SR, when present in the same cells or at least at the same synapse, do not work in isolation: their activities are regulated in opposite ways by the gaseous transmitter nitric oxide (NO) [31,32]. NO inhibits SR [31] but enhances DAAO activities [32], thus tightly controlling the levels of D-serine in glia. In turn, D-serine might inhibit NO synthase in glia [31]. Owing the importance of NO at glutamatergic synapses [33], these findings, although preliminary, might have important functional consequences: they imply that NO is a potential switch-off signal that orchestrates the termination of D-serine signalling (Figure 2). How do astrocytes regulate synaptic D-serine? As yet, there is no consensus about how astrocytes regulate D-serine levels at synapses. Pioneer experiments conducted on astrocytes in culture revealed that activation of non-NMDA receptors, notably AMPA/kainate subtype glutamate receptors, is the main stimulus triggering the efflux of D-serine from these cells [27] (Figure 2). However, we still do not know whether this occurs in vivo. In the rat striatum for example, no changes in D-serine extracellular concentrations were noted in response to application of different agonists and antagonists of glutamate receptors, particularly those of AMPA/kainate receptors, which were effective at modulating ambient levels of glutamate [34]. Still, in vitro activation of AMPA/kainate and metabotropic receptors can trigger release of D-serine from astrocytes that depends on Ca2+ and the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) [35]. Inhibition of the vacuolar proton ATPase reduced D-serine release, probably by disrupting the uptake of the amino acid into vesicles. These results are consistent with vesicular storage and release of D-serine and support the existence of specific storing organelles and a vesicular transport mechanism that has yet to be identified (Figure 2). Recent observations have already shown that astrocytes release glutamate and ATP through Ca2+-dependent exocytosis [4,36,37], as would be expected to occur for D-serine. Glial D-serine and glutamate releases are affected to the same extent by tetanus neurotoxin, Ca2+ removal and inhibition of vesicular uptake, supporting the idea that the release of these two gliotransmitters shares common features. Are glutamate and D-serine co-stored and/or coreleased? D-Serine immunoreactivity has indeed been found in vesicles bearing the vesicular transporter for glutamate [35]. Furthermore, activation of glutamate receptors causes the release not only of glutamate but also of D-serine [35,37]. It is not yet known whether there is a strict interplay between D-serine and glutamate but storage of these two gliotransmitters in the same vesicles would represent the perfect cocktail to activate NMDA receptors. Nevertheless, Ca2+-dependent vesicular release of D-serine from glia does not exclude the possibility that the amino acid is released via other mechanism, especially considering that the majority of D-serine is free in the www.sciencedirect.com

cytoplasm [23,35]. This would fit with the report that transfection of GRIP into astrocytes dramatically increases the basal and the AMPA-evoked efflux of D-serine with no apparent storage [23]. There is mounting evidence that astrocytes can use a chemical gradient to drive the release of cytosolic ATP and glutamate through activated P2X7 receptors, hemichannels or anion channels [4]. One can imagine that a similar phenomenon might account for efflux of cytosolic D-serine. In addition, release of cytosolic D-serine can operate through neutral amino acid transporters present on the membrane of astrocytes [38]. In primary cultures, D-serine fluxes are coupled to counter-movements of Lserine and, to a lesser extent, of other small neutral amino acids, suggesting an antiporter mechanism for D-serine transport (Figure 2). In this context, efflux of preloaded Dserine is induced by physiological concentrations of L-serine more efficiently than by kainate, with features of the Na+dependent B-type alanine–serine–cysteine transporter (ASCT) system [38]. Whether the vesicular and/or nonvesicular pathways are involved in the release of glial Dserine, and which of these occurs in vivo, awaits investigation. However, glia do not constitute a unique releasable source of D-serine. Indeed, Ciriacks and Bowser [34] have noted that in vivo activation of NMDA receptors induces release of D-serine in the rat striatum even though rat astrocytes do not express these receptors [39]. The secondary source of D-serine might be neurons, at least in some regions of the brain [13,16]. Indeed, a recent study has shown that neurons of the cerebral cortex can release Dserine upon activation of glutamate receptors, notably NMDA receptors [16]. Nevertheless, it seems that the neuronal release of D-serine is of non-vesicular origin, in contrast to the glial release [16] (Figure 2). Similar to the action of others neurotransmitters, that of D-serine normally should be terminated by its clearance from the synaptic cleft by transporter proteins expressed by neurons and/or glia. Several candidate transporters for D-serine have been identified on the membranes of glia and neurons [40–44]. Glia express a Na+-dependent transporter that has low affinity for D-serine and L-serine [40], the characteristics of which resemble those of the ASCT system, which carries D-serine in cultured astrocytes and in isolated retina [38,43]. Another neutral amino acid transporter, which is Na+-independent, has also been identified. The alanine–serine–cysteine transporter 1 (Asc-1) has a high affinity for D-serine and is confined to the presynaptic terminals, dendrites and somata of neurons. The cellular localization of Asc-1 suggests that this transporter contributes to the synaptic clearance of D-serine by neurons [45,46]. Finally, a novel Na+–Cl-sensitive transporter has been described in rat brain synaptosomes [41,42]. In contrast to the ASCT system, which has broad substrate selectivity, this serine transporter has limited affinity for other neutral amino acids including cysteine and alanine. It is conceivable, therefore, that multiple transport systems contribute simultaneously to the regulation of D-serine concentrations at the synapse (Figure 2). D-Serine, an active modulator of synaptic transmission A key advance in our appreciation of the role of D-serine in the CNS derives from observations that D-serine is found in

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astrocytes that ensheathe NMDA-receptor-bearing neurons and that levels of D-serine parallel the ontogeny of these receptors [33,47]. In vitro studies teach us that Dserine is released from astrocytes upon activation of their glutamatergic receptors [27]. All these observations strongly suggest that, in some regions of the brain, glutamate released from the nerve terminal triggers glial Dserine efflux, which in turn modulates the NMDA receptors at postsynaptic sites (Figure 2). The hippocampus provides an exquisite model for studying the function of D-serine because high densities of D-serine and NMDA receptors occur in the subiculum and CA1 and CA3 regions [47]. In culture preparations of hippocampal neurons, specific enzymatic degradation of released D-serine by exogenously applied DAAO considerably reduces agonist-evoked and spontaneous NMDA-receptor-driven currents (Box 1). The hippocampus is one site where long-term potentiation (LTP) relies on NMDA receptor activation [48]. Therefore, because D-serine is an endogenous ligand for NMDA receptors, it was not surprising to discover that D-serine release from astrocytes is involved in the induction of LTP in CA1 pyramidal cell synapses [49]. Pre-treatment using exogenous DAAO inhibited this LTP, further supporting the idea

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that D-serine, rather than glycine, is the endogenous ligand of NMDA receptors in this area of the brain. It is commonly believed that senescence is associated with impaired NMDA-receptor-dependent synaptic plasticity and notably LTP [50]. In line with the crucial role of D-serine in synaptic plasticity, defective LTP recorded in a senescence-accelerated mouse strain was rescued to control levels when Dserine was given as a supplement [51]. However, this study did not address the molecular and cellular mechanisms underlying these synaptic plasticity deficiencies or the link with metabolism of D-serine. This has been addressed recently [52] with the finding that deficient LTP in senescent rats is due primarily to a significant reduction in the production of D-serine rather than to a diminution in density of D-serine-binding sites or affinity of D-serine for NMDA receptors. Furthermore, in agreement with the emerging role of D-serine as the major ligand for the modulatory glycine-binding site of NMDA receptors, such a deficit in LTP is not associated with reduced levels of glycine [52]. The ability of D-serine to control NMDAreceptor-dependent neurotransmission has been confirmed using DAAO-deficient mice. The highest increases in D-serine levels displayed by these mice are in the

Box 1. The NMDA receptor with its modulatory sites – the role of D-serine NMDA-sensitive ionotropic glutamate receptors are tetrameric complexes formed by the assembly of two subunits [67,88]. Three subunit families, designated NR1, NR2 and NR3, have been cloned [89]. NR1 occurs as eight distinct isoforms owing to three independent sites for alternative splicing. NR2 and NR3 families consist of four and two subunits respectively that have several splice variants. Each subunit exhibits four functional domains (Figure Ia). The C-terminal domain (CTD) is the locus of numerous protein–protein interactions determining trafficking and the synaptic organization of the receptor [88]. The channel pore is formed by three transmembrane domains (TMD) and a hairpin bend within the membrane. The N terminus and the loop between the two transmembrane domains nearest to it contain the S1–S2 region, which forms the binding pocket for agonists [67,88–92]. Most functional NMDA receptors in the mammalian CNS are formed by the combination of NR1 and NR2 subunits, containing the coagonist and glutamate recognition sites, respectively (Figure Ia). NR3 subunits can assemble with NR1–NR2 complexes to depress NMDA receptor responses [93]. At resting membrane potentials, the NMDA

receptor channel is blocked by Mg2+; depolarization removes this block and enables ion flux when the channel binds glutamate and the co-agonist. NMDA receptors are permeant to Ca2+, Na+ and K+. Protons and polyamines such as spermine and spermidine bind to the N-terminal domain (NTD) to increase permeability of the receptor complex to cations. In addition, most NMDA receptors are inhibited by Zn2+ in a voltage-dependent manner and are influenced by oxidation–reduction state of the NR1 subunit. Although glycine has generally been assumed to be the co-agonist for glutamate at NMDA receptors [94,95], it is now obvious that D-serine can substitute for glycine to activate these receptors. The crystal structure of the NR1 S1–S2 ligand-binding core reveals that binding of D-serine is similar to that of glycine and involves the same electrostatic interactions with side chains of Arg523 and Asp732 in the loop [91] (Figure Ib). Direct demonstration that D-serine produced in the brain can activate NMDA receptors is derived from the observations that application of purified D-amino acid oxidase (DAAO), the D-serine degrading enzyme, decreased NMDA-induced currents [54] (Figure Ic).

Figure I. Allosteric modulation of NMDA receptors by D-serine. (a) Model of the NR1 and NR2 NMDA receptor subunits, depicting functional domains and binding sites. (b) Amino acids involved in binding of D-serine (DS) to NR1. (c) Application of DAAO decreases NMDA-induced currents. Additional abbreviation: ABD, agonist-binding domain. Panels (a), (b) and (c) are modified, with permission, from Refs [67], [91] and [54], respectively. www.sciencedirect.com

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brainstem and spinal cord [53]. As expected, NMDA-receptor-mediated excitatory postsynaptic currents recorded from spinal cord dorsal horn neurons were significantly potentiated in mutant mice [53]. Finally, knockout mice for the neuronal transporter Asc-1 display NMDA-receptordependent hyperexcitability, presumably resulting from elevated extracellular D-serine levels [44]. The fact that D-serine is present in a subset of neurons [13,16] would fit perfectly with the presence of Asc-1 at the surface of neurons. Electrophysiological data obtained in the hippocampus [54] have shown that the level of occupancy of the NMDA receptor glycine-binding site is higher at synaptic than at extrasynaptic receptors. Whether this is related to the existence of microdomains for gliotransmitter release, to the proximity of synaptically released glutamate triggering D-serine release, or both, remains to be determined. Glia have functional compartments or microdomains where localized high increases in Ca2+ concentration occur; these tightly enwrap synapses and contain the vesicles for glutamate [4,37]. By analogy to glutamate, it is tempting to speculate that D-serine is released from fine glial processes that contact synapses bearing NMDA receptors. From the preceding discussion, it is obvious that astrocytic D-serine modulates NMDA-receptor-dependent neurotransmission and synaptic plasticity in the CNS. D-Serine might also be involved in the coding and processing of sensory information. For example, in the retina, SR localized in radial Mu¨ller glia controls NMDA-receptormediated responses resulting from application of NMDA or light stimulation, through the production of D-serine [55]. Another potential model is the peripheral vestibular system, where there are high levels of SR, DAAO and D-serine in the sensory epithelia [56]. Finally, and not at least importantly, astrocytes are not the only glia that synthesize and release D-serine: microglia do too [14]. The function of D-serine secreted by quiescent microglia is not yet known. But there is growing evidence that neurons in nonpathological states are frequently contacted by satellite microglia, which might promote synaptogenesis and synaptic plasticity using a large repertoire of secreted factors, such as brain-derived neurotrophic factor (BDNF) or neurotrophin 3 (NT-3) [57]. D-Serine, a motility-promoting signal during development Radial migration of immature granule cells in the developing cerebellum is one of the best-characterized instances of the participation of NMDA receptors in neuronal migration [58]. As they migrate through the molecular layer, immature neurons are guided by Bergmann glia (Figure 3). Real-time observation of cell migration in acute cerebellar slices revealed that glutamate, acting on NMDA receptors, has a crucial, modulatory effect on promoting the motility of granule cells through the molecular layer [59]. Evidence includes that granule cells start their radial migration after the expression of the NMDA receptors on the plasmalemmal surface, and that antagonists of these receptors significantly decrease the rate of glia-guided radial neuronal migration. By contrast, the rate of granule cell movement is increased by removal of Mg2+ or by application of www.sciencedirect.com

NMDA or the co-agonist glycine [59]. How NMDA receptors of migrating immature neurons are activated remains controversial because migrating neurons do not form synapses before complete translocation to the internal granule layer. An attractive hypothesis is that glutamate released by Bergmann glia activates immature NMDA receptors in a non-synaptic, paracrine mode [59]. Might D-serine have a role in this? In fact, SR is present in the Bergmann glia of the developing cerebellum (Figure 3) and D-serine levels peak at postnatal day (P)14, the time of intense granule cell migration, and subsequently diminish [33]. D-Serine released by Bergmann glia seems to be essential in promoting the migration of granule cells through activation of NMDA receptors [23]. Inhibition of SR, using a new series of specific inhibitors or by applying DAAO on cerebellar slices to degrade extracellular released D-serine, blocked the migration of granule cells via inhibition of NMDAreceptor-mediated Ca2+ influx [23]. In addition, GRIP adenoviral infection of the developing cerebellum increases Dserine levels through activation of SR (Figure 2) and concomitantly increases the rate at which granule cells migrate to their final location. D-Serine might also participate in the maturation (i.e. synaptogenesis) of developing neural network because its ontogeny in Bergmann glia parallels expression of the NR2A and NR2B NMDA receptor subunits in Purkinje cells [47]. The motility-promoting role of D-serine is probably not restricted to the postnatal development of the cerebellum. Indeed, SR is present in the perireticular nucleus, a transient area of the human foetal brain that is thought to be involved in the guidance of corticofugal and thalamocortical fibres [60]. Additionally, D-serine synthesized in the placenta is exported into the foetal circulation through the amino acid transporter ATB [61]. NMDA receptors are present early during gestation [62], so D-serine is well positioned both spatially and temporally to control NMDA-receptor-mediated neuronal migration and synaptogenesis. Because blocking NMDA receptors during neocorticogenesis [63] or genetically induced alterations in these receptors [64] results in severe abnormal cortical development, disrupting D-serine metabolism during embryonic and early postnatal life might lead to the same developmental defects. Notably, impairment in cerebellar development and maturation fits with a specific shut-down of DAAO gene expression [65], supporting the hypothesis that alteration in the signalling of D-serine and/or NMDA receptors promotes neuronal degeneration and inhibition of synaptogenesis. But, D-serine, a pro-death signal Should we conclude that D-serine is a good Samaritan that subtly regulates NMDA receptor activity? It is well known that NMDA receptors can cause cell death in many neuropathological conditions when they are intensely or chronically activated [66–68]. Increased extracellular levels of glutamate, resulting from downregulation of its uptake system [69] or from active release [70], are the primary cause of neuronal death following excessive NMDA receptor activation [68]. Because D-serine regulates NMDA receptor activity, and glia are suspected to support

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Figure 3. Granule cell migration during postnatal development of the cerebellum, and its regulation by D-serine. (a) In the early postnatal cerebellum, granule cells migrate from the germinal zone, represented by the external granule cell layer (EGL), to the inner granule cell layer (IGL) and Purkinje cell layers. The migrating cells adopt two types of trajectory. In the EGL (stages 1–5), immature granule cells migrate tangentially to the bottom of the layer. During their tangential migration, they extend two horizontal processes near the top of the EGL and develop a vertical process when approaching the border between the EGL and the molecular layer (ML). In the ML (stages 6–8), granule cells undergo radial migration along the processes of Bergmann glia (Bg). In stages 9–11, granule cells migrate radially in the IGL, independently of glia, completing their migration in the middle or the bottom of the layer. Additional abbreviations: G, Golgi cell; g, postmigratory granule cell; P, Purkinje cell. (b) Relationship between the activity of granule cell NMDA receptors and the position of the granule cells along the migratory pathway. The histogram represents the mean frequency (SEM) of spontaneous NMDA receptor channel activity in the EGL, ML + PCL and IGL of developing cerebellar slices. (c–e) D-Serine released by Bergmann glia triggers the radial migration of granule cells in cerebellar explants. DAAO and SR inhibitors decrease granule cell migration. (c) Pretreatment of cerebellar slices with DAAO before the migration assay (white bars) or continuous treatment with DAAO (grey bars) considerably affects granule cell migration. D-Serine and sodium benzoate (NaBENZ), an inhibitor of DAAO, rescue granule cell migration from the inhibitory effect of DAAO. (d) Phenazine methosulfate (Met-Phen) and phenazine ethosulfate (Et-Phen), two inhibitors of SR, block granule cell migration whereas phenazine exerts modest inhibitory effects. The inhibitory effects of SR inhibitors are reversed by adding D-serine. (e) Inhibiting SR blocks granule cell Ca2+ transients in three different cells (1,2 and 3), most likely through reduction of NMDA receptor activity [59]. Panels (a), (b) and (c–e) were modified with permission from Refs [59], [96] and [23], respectively.

the development of neurotoxicity [71,72], D-serine might compromise neuronal survival and function by exacerbating the effect of glutamate when its extracellular levels are altered. Research over the past two years has offered much credibility to this notion, particularly in relation to two pathological conditions. Various lines of evidence support a central role of amyloid b-peptide (Ab), the major component of neuritic plaques, in the pathogenesis of Alzheimer disease (AD) [73]. Ab causes an inflammatory phenotype in microglia, which in turn triggers neuronal death by excitotoxicity [15,73,74]. Furthermore, the activity of NMDA receptors is increased in the AD brain and memantine, an antagonist with moderate affinity for these receptors, is neuroprotective [68]. Recent observations also support the idea that D-serine might participate in the pathogenic signatures of AD, excitotoxicity and neuroinflammation. Indeed, it has been discovered that the hippocampus of AD patients displays higher SR activity and that Ab can stimulate, in vitro, the synthesis and the release of neurotoxic levels of D-serine www.sciencedirect.com

from microglia [14] (Figure 4). Conversely, DAAO can protect neurons against Ab-induced Ca2+ overload and neurotoxicity, thus providing evidence that D-serine is a death signal induced by Ab [14]. How does Ab stimulate SR activity? Analysis of the first intron of the SR gene reveals the presence of several activator protein-1 (AP-1)-binding sites for transcriptional regulation [15]. Deletion and sitespecific mutagenesis show that two AP-1-binding sites are, in fact, responsible for responsiveness to Ab and to lipopolysaccharide (LPS), another relevant proinflammatory stimulus [14,15] (Figure 4). These proinflammatory stimuli induce transcription of SR through activation of the Jun Nterminal kinase (JNK) pathway, implicating c-Fos and JunB as the interacting proteins at the AP-1 sites [15]. Ab provokes Ca2+ transients in microglia [75] and might therefore also regulate the activity of SR at a post-translation level, because the enzyme activity is influenced by Ca2+ [20]. All these in vitro observations fit with the dramatic increase in D-serine levels measured in the cerebrospinal fluid of AD patients [76]. Nevertheless, no

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Figure 4. Role of glial-derived D-serine in the neurotoxicity associated with neuroinflammation. (a) Schematic model. Normally, glia (microglia and astrocytes) are quiescent. Chronic CNS inflammation in Alzheimer’s disease, caused by the amyloid b-peptide (Ab) or acute inflammation by the endotoxin lipopolysaccharide (LPS), activates glia (1), leading to release of cell-death mediators such as glutamate, cytokines and/or reactive oxygen species (ROS) [71,74] (2). In addition, inflammatory stimuli such as Ab and LPS stimulate serine racemase (SR) transcription through two AP-1 elements present in the upstream region of the SR promoter. Increased SR transcription leads to generation and efflux of deleterious levels of D-serine [14,15] (2). Subsequent to its release, D-serine exacerbates the effects of glutamate at synapses, leading to neuronal damage through over-activation of NMDA receptors (3), causing Ca2+ overload [14,15] and strong mitochondrial ROS generation. Oxygen free radicals contribute to membrane lipid peroxidation, damage to DNA and proteins, and production of inflammatory mediators (4) that can in turn reinforce the inflammation reciprocally (5). This model of disrupted glia-to-neuron D-serine signalling might be associated with inflammation resulting from ischemia [83,84] or from opioid (morphine) administration [81]. Blue text represents the prime pathological stimuli, and red text the downstream cascades leading to neuron death. (b) Results supporting the model in (a). (i) Enhanced activity of SR regulatory elements (AP-1) in response to LPS. (ii) Enhanced D-serine levels in microglial culture medium in response to Ab or LPS. (iii) Chromatograms obtained from control microglia and Ab-treated microglia media illustrate accumulation of D-serine. (iv) Ab(1–42)-activated microglia induce neurotoxicity and this deleterious effect on hippocampal neurons is prevented by treatment of the cultures with DAAO. Photomicrographs document neuronal integrity over 24 h. Results in (b,i,ii) and chromatograms in (b,iii) are modified, with permission, from Refs [14,15]; photographs in (b,iv) are reproduced courtesy of Steve Barger [14].

change has been noted in D-serine levels in the brain parenchyma or serum of such patients [77,78]. The apparent discrepancy between the different studies might be multi-factorial. Notably, levels of D-serine itself might be expected to increase early in AD progression; thus, any elevation might be difficult to detect after the disease has progressed to its final stages. The demonstration that Ab activates the JNK-mediated modulation of AP-1-binding activity might have more general repercussions for our understanding of other neurodegenerative and inflammatory diseases. Considerable data have shown that JNK is a crossroads for cellular stress and apoptosis-inducing stimuli [79], and agents targeting this pathway are neuroprotective [80]. In this context, the recent report that acute morphine administration in rats [81] increases expression of SR transcripts illustrates this notion, as does the finding that the AP-1–JNK signalling pathway is activated in analgesia [82]. Ischemia provides another pathological situation for studying the role of D-serine in neuroinflammation and excitotoxicity. Exposing neurons to oxygen-free and glucose-free conditions (simulated ischemia) causes NMDAreceptor-dependent cell death that is prevented by NMDA receptor antagonists [66,68]. Katsuki et al. have provided evidence that endogenous D-serine has a significant role in neuronal damage resulting from simulated ischemia [83]: application of DAAO to ischemic brain slices protected neurons from death, probably by reducing extracellular www.sciencedirect.com

D-serine levels, although D-serine levels were not monitored in this study. Katsuki et al. have also demonstrated a protective effect of exogenous DAAO against NMDAinduced excitotoxicity. This is consistent with the recent report by Wolosker and colleagues [84] that D-serine deaminase offers protection against NMDA-induced neuronal insults by shutting-down the activity of NMDA receptors to physiological levels. Nevertheless, these studies did not address the source (astrocytes, microglia and/or neurons) of D-serine and the mechanisms leading to deleterious extracellular levels of the amino acid. It is plausible that in these cell types, ischemia and NMDA might upregulate SR expression, and induce release of excessive amounts of D-serine. It has been shown that extrasynaptic NMDA receptors trigger neuronal death by shutting-off the pro-survival activity of cAMP-response-element-binding protein (CREB), whereas synaptic NMDA receptor activation promotes the survival of neurons by opposing a positive action on CREB activity [66]. A major focus for future work will be to define whether this is the molecular basis for the excitotoxic influence of D-serine when present in excess.

Concluding remarks Recent literature has unveiled multiple roles for D-serine in the brain. This atypical amino acid can serve as a gliotransmitter that modulates neurotransmission at glutamatergic synapses, and is a motility-promoting signal important for

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development and maturation of the CNS. However, it can also cause cell death when in excess, through overactivation of NMDA receptors in neuropathological conditions. The features of D-serine activity thus parallel those of NMDA receptors. Of course, many questions remain unsolved. Is too little D-serine also deleterious for neurons? This is likely, because hypofunction of NMDA receptors render neurons more vulnerable to trauma and causes apoptosis during development [66], and D-serine metabolism deficiency is linked to the etiology of schizophrenia [25,85,86]. Although much evidence strongly supports the notion that D-serine is a major endogenous ligand for the glycinebinding site of NMDA receptors, this does not mean that glycine is not also a ligand. Clearly, ambient glycine levels would be sufficient in most brain areas to account for NMDA receptor activation, and genetically targeted inactivation of glycine transporters leads to major changes in glutamate-mediated synaptic transmission [87]. There remains much to be done to delineate the respective contributions of D-serine and glycine at glutamatergic synapses in physiological and pathological conditions. It is a fascinating but complicated task, because there are many NMDA receptor subtypes and these all have intrinsic properties that control their trafficking, their pharmacological features and their expression during development. In addition, NMDA receptors are central to many physiological and pathological signalling events. Use of genetic animal models to disrupt D-serine metabolism and the development of new tools to visualize D-serine and glycine in vivo should aid the translation of our cell biological knowledge into a more physiological context, and help to define the role of each agonist in regulating NMDA-receptor-dependent cell death, cell survival or physiological pathways. Acknowledgements We thank Drs Dionysia Theodosis and Elisabeth Traiffort for graciously providing critical readings of the manuscript. We also acknowledge Lydie Collet and Marielle Rimard for their technical assistance in preparing the figures. We apologize to those whose work we were unable to cite owing to space limitations. J.P.M. is supported by grants from the CNRS and Servier laboratories. M.M. is a recipient of a PhD fellowship from the ‘Ministe`re de l’Enseignement, de la Recherche et de la Technologie’.

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