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D-Amino Acids pp 27–50Cite as

Physiological Roles of d-Serine in the Central Nervous System

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Abstract

The N-methyl d-aspartic acid receptors (NMDARs) are key glutamate receptors that transduce glutamatergic signals throughout the developing and adult central nervous system (CNS). Despite diversity in their subunit composition, their subcellular localization, and their biophysical and pharmacological properties, activation of NMDARs always requires in addition to glutamate the binding of a co-agonist that has long been thought to be glycine. However, research over the last two decades has challenged this long-cherished model by showing that the d-isomer of serine is the preferential co-agonist for a large population of NMDARs in many areas of the adult brain. Nowadays, a totally new picture of glutamatergic synapses is emerging where both glycine and d-serine are involved in a complex interplay to regulate NMDAR functions in the CNS following time and space constraints. In this review, we focus on the particular contribution of d-serine relatively to glycine in orchestrating synapse formation, dynamics, and neuronal network activity in a time- and synapse-specific manner and its role in cognitive functions. We will discuss also how astroglia and neurons use different pathways to regulate levels of extracellular d-serine and how alterations in synaptic availability of this d-amino acid may contribute to cognitive deficits associated to healthy aging and therefore may open new avenues for therapies.

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Acknowledgments

We thank our collaborators who help to expand the field. We apologize to our colleagues whose work could not be cited due to space limitations. Work in Dr Mothet’s lab is supported by operating grants from the Centre National de la Recherche Scientifique, France Alzheimer, the Fondation pour la Recherche Médicale, Direction Générale de l’Armement and the Université Aix-Marseille.

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Authors and Affiliations

  1. Team ‘Gliotransmission and Synaptopathies’, CRN2M UMR7286, Aix-Marseille Université, CNRS, 13344 cedex 15, Marseille, France

    Jean-Pierre Mothet & Grégoire Mondielli

  2. Interdisciplinary Institute for Neuroscience, UMR 5297, University of Bordeaux and Centre National de la Recherche Scientifique, F-33000, Bordeaux, France

    Magalie Martineau

Authors
  1. Jean-Pierre Mothet
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  2. Grégoire Mondielli
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  3. Magalie Martineau
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Correspondence to Jean-Pierre Mothet .

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Editors and Affiliations

  1. Department of Applied Molecular Biosciences Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan

    Tohru Yoshimura

  2. Department of Psychiatry and Behavioral Sciences Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

    Toru Nishikawa

  3. Laboratory of Biomolecular Science Department of Pharmaceutical Life Sciences, Kitasato University, Tokyo, Japan

    Hiroshi Homma

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Mothet, JP., Mondielli, G., Martineau, M. (2016). Physiological Roles of d-Serine in the Central Nervous System. In: Yoshimura, T., Nishikawa, T., Homma, H. (eds) D-Amino Acids. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56077-7_3

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