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d-Serine, the Shape-Shifting NMDA Receptor Co-agonist

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Abstract

Shape-shifting, a phenomenon wide-spread in folklore, refers to the ability to physically change from one identity to another, typically from an innocuous entity to a destructive one. The amino acid d-serine over the last 25 years has “shape-shifted” into several identities: a purported glial transmitter activating N-methyl-d-aspartate receptors (NMDARs), a co-transmitter concentrated in excitatory glutamatergic neurons, an autocrine that is released at dendritic spines to prime their post-synaptic NMDARs for an instantaneous response to glutamate and an excitotoxic moiety released from inflammatory (A1) astrocytes. This article will review evidence in support of these scenarios and the artifacts that misled investigators of the true identity of d-serine.

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Acknowledgements

Some of the research described in this review was supported by R01MH05190 and P50MH0G0450 to JTC and by Whitehall Foundation (#2018–05-107), BrightFocus Foundation (A2019034S), 1R03AG063201-01 (NIA), and a subcontract of R01NS098740-02 to DB. JTC reports consulting with Concert Pharm and holding a patent on D-serine for the treatment of serious mental illness, which is owned by Massachusetts General Hospital. DB and HW report no conflict of interests. We thank J-P Mothet for his helpful suggestions about the manuscript.

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Authors and Affiliations

  1. Department of Psychiatry, Harvard Medical School and McLean Hospital, Belmont, MA, 02478, USA

    Joseph T. Coyle & Darrick Balu

  2. Translational Psychiatry Laboratory, McLean Hospital, Belmont, MA, 02478, USA

    Darrick Balu

  3. Technion Israel Institute of Technology, Haifa, Israel

    Herman Wolosker

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  1. Joseph T. Coyle
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  2. Darrick Balu
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  3. Herman Wolosker
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Correspondence to Joseph T. Coyle.

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This review is dedicated to Michael B Robinson, PhD, Professor of Pharmacology and Pediatrics at Perelman School of Medicine at the University of Pennsylvania, who spent the years of 1985–1989 as a post-doctoral fellow in the Coyle laboratory in the Department of Neuroscience at Johns Hopkins School of Medicine and played a seminal role in the laboratory’s 45-year-long research program on the role of glutamatergic neurotransmission in health and disease.

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Coyle, J.T., Balu, D. & Wolosker, H. d-Serine, the Shape-Shifting NMDA Receptor Co-agonist. Neurochem Res 45, 1344–1353 (2020). https://doi.org/10.1007/s11064-020-03014-1

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  • DOI: https://doi.org/10.1007/s11064-020-03014-1

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