Trends in Neurosciences
Volume 29, Issue 8, August 2006, Pages 481-491
Journal home page for Trends in Neurosciences

Review
d-Serine signalling in the brain: friend and foe

https://doi.org/10.1016/j.tins.2006.06.008Get rights and content

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 neuron-derived 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 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.

Section snippets

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 5′-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, 10, 11 (Figure 1a). The distribution of SR is very similar to that

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

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 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 d-serine 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

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

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, 67, 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

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 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

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 ‘Ministère de l’Enseignement, de la Recherche et de la Technologie’.

References (96)

  • K. Strisovsky

    Mouse brain serine racemase catalyzes specific elimination of l-serine to pyruvate

    FEBS Lett.

    (2003)
  • Y. Urai

    Gene expression of d-amino acid oxidase in cultured rat astrocytes: regional and cell type specific expression

    Neurosci. Lett.

    (2002)
  • K. Shoji

    Regulation of serine racemase activity by d-serine and nitric oxide in human glioblastoma cells

    Neurosci. Lett.

    (2006)
  • K. Shoji

    Mutual regulation between serine and nitric oxide metabolism in human glioblastoma cells

    Neurosci. Lett.

    (2006)
  • C.M. Ciriacks et al.

    Measuring the effect of glutamate receptor agonists on extracellular d-serine concentrations in the rat striatum using online microdialysis-capillary electrophoresis

    Neurosci. Lett.

    (2006)
  • S. Coco

    Storage and release of ATP from astrocytes in culture

    J. Biol. Chem.

    (2003)
  • C.S. Ribeiro

    Glial transport of the neuromodulator d-serine

    Brain Res.

    (2002)
  • F. Hayashi

    Uptake of d- and l-serine in C6 glioma cells

    Neurosci. Lett.

    (1997)
  • D.C. Javitt

    A novel alanine-insensitive d-serine transporter in rat brain synaptosomal

    Brain Res.

    (2002)
  • K.B. O’Brien

    d-Serine uptake by isolated retinas is consistent with ASCT-mediated transport

    Neurosci. Lett.

    (2005)
  • X. Xie

    Lack of the alanine-serine-cysteine transporter 1 causes tremors, seizures, and early postnatal death in mice

    Brain Res.

    (2005)
  • H. Matsuo

    High affinity d- and l-serine transporter ASC-1: cloning and dendritic localization in the rat cerebral and cerebellar cortices

    Neurosci. Lett.

    (2004)
  • S. Yang

    d-serine enhances impaired long-term potentiation in CA1 subfield of hippocampal slices from aged senescence-accelerated mouse prone/8

    Neurosci. Lett.

    (2005)
  • K. Wake

    Exaggerated responses to chronic nociceptive stimuli and enhancement of N-methyl-d-aspartate receptor-mediated synaptic transmission in mutant mice lacking d-amino-acid oxidase

    Neurosci. Lett.

    (2001)
  • D. Dememes

    Cellular distribution of d-serine, serine racemase and d-amino acid oxidase in the rat vestibular sensory epithelia

    Neuroscience

    (2006)
  • L.M. Ritter

    Ontogeny of ionotropic glutamate receptor expression in human fetal brain

    Dev. Brain Res.

    (2001)
  • S. Taharaguchi

    Impaired development of the cerebellum in transgenic mice expressing the immediate-early protein IE180 of pseudorabies virus

    Virology

    (2003)
  • G.E. Hardingham et al.

    The Yin and Yang of NMDA receptor signalling

    Trends Neurosci.

    (2003)
  • S.A. Lipton

    Failures and successes of NMDA receptor antagonists: molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults

    NeuroRx

    (2004)
  • V. Silei

    Activation of microglial cells by PrP and β-amyloid fragments raises intracellular calcium through L-type voltage sensitive calcium channels

    Brain Res.

    (1999)
  • Y. Nagata

    Free d-serine concentration in normal and Alzheimer human brain

    Brain Res. Bull.

    (1995)
  • K. Hashimoto

    Possible role of d-serine in the pathophysiology of Alzheimer's disease

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2004)
  • M. Yoshikawa

    Acute treatment with morphine augments the expression of serine racemase and d-amino acid oxidase mRNAs in rat brain

    Eur. J. Pharmacol.

    (2005)
  • H. Doya

    c-Jun N-terminal kinase activation in dorsal root ganglion contributes to pain hypersensitivity

    Biochem. Biophys. Res. Commun.

    (2005)
  • M.J. Owen

    Schizophrenia: genes at last?

    Trends Genet.

    (2005)
  • K. Prybylowski et al.

    N-Methyl-d-aspartate receptors: subunit assembly and trafficking to the synapse

    J. Biol. Chem.

    (2004)
  • S. Cull-Candy

    NMDA receptor subunits: diversity, development and disease

    Curr. Opin. Neurobiol.

    (2001)
  • B. Foucaud

    Structural model of the N-methyl-d-aspartate receptor glycine site probed by site-directed chemical coupling

    J. Biol. Chem.

    (2003)
  • A. Inanobe

    Mechanism of partial agonist action at the NR1 subunit of NMDA receptors

    Neuron

    (2005)
  • D.J. Rossi et al.

    The developmental onset of NMDA receptor-channel activity during neuronal migration

    Neuropharmacology

    (1993)
  • R. Ventura et al.

    Three-dimensional relationships between hippocampal synapses and astrocytes

    J. Neurosci.

    (1999)
  • P.G. Haydon

    Glia: listening and talking to the synapse

    Nat. Rev. Neurosci.

    (2001)
  • A. Volterra et al.

    Astrocytes, from brain glue to communication elements: the revolution continues

    Nat. Rev. Neurosci.

    (2005)
  • S.H. Oliet

    Glial modulation of synaptic transmission: Insights from the supraoptic nucleus of the hypothalamus

    Glia

    (2004)
  • M.J. Schell

    The N-methyl d-aspartate receptor glycine site and d-serine metabolism: an evolutionary perspective

    Philos. Trans. R. Soc. Lond. B Biol. Sci.

    (2004)
  • H. Wolosker

    Serine racemase: a glial enzyme synthesizing d-serine to regulate glutamate-N-methyl-d-aspartate neurotransmission

    Proc. Natl. Acad. Sci. U. S. A.

    (1999)
  • S.M. Williams

    Immunocytochemical analysis of d-serine distribution in the mammalian brain reveals novel anatomical compartmentalizations in glia and neurons

    Glia

    (2006)
  • S.Z. Wu

    Induction of serine racemase expression and d-serine release from microglia by amyloid β-peptide

    J. Neuroinflammation

    (2004)
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