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d-Serine Signaling and Schizophrenia

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D-Amino Acids

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Abstract

It has been widely accepted that the hypofunction of the N-methyl-d-aspartate-type glutamate receptor (NMDAR) may be implicated in the pathophysiology of both positive- and negative-cognitive symptomatologies of schizophrenia because NMDAR antagonists, including phencyclidine (PCP) and anti-NMDAR antibodies, mimic these respective antipsychotic-responsive and antipsychotic-resistant symptoms. d-Serine and other agonists for the glycine modulatory site of the NMDAR, which facilitate the receptor function, are found to not only inhibit behavioral models of schizophrenia and hyperdopaminergic transmission caused by schizophrenomimetics, PCP, and amphetamines, in experimental animals, but also ameliorate the entire extent of the above schizophrenic symptoms. Moreover, d-serine has been revealed to be a brain-enriched endogenous substance displaying an NMDAR-like distribution. At least, in the forebrain areas, the NMDAR function levels are under control of the extracellular d-serine concentrations that are regulated in a different manner from that of classical neurotransmitters by neuronal and glial activities, the calcium-permeable AMPA receptor, the Asc-1 neutral amino acid transporter, and the neuronal serine racemase, a d-serine synthesizing enzyme. These findings raise the possibility that insufficient extracellular d-serine signaling could be a part of a key factor that leads to the presumed hypofunction of the NMDAR in schizophrenia. Further investigations on the molecular and cellular mechanisms of the d-serine metabolism and their alterations in schizophrenia may contribute to the elucidation of the pathophysiology of and development of a novel therapeutic approach to this intractable mental disorder.

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  1. Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

    Toru Nishikawa

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  1. Toru Nishikawa
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Correspondence to Toru Nishikawa .

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  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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© 2016 Springer Japan

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Nishikawa, T. (2016). d-Serine Signaling and Schizophrenia. In: Yoshimura, T., Nishikawa, T., Homma, H. (eds) D-Amino Acids. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56077-7_6

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