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Role for neonatal D-serine signaling: prevention of physiological and behavioral deficits in adult Pick1 knockout mice

Molecular Psychiatry volume 21, pages 386–393 (2016)Cite this article

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Abstract

NMDA glutamate receptors have key roles in brain development, function and dysfunction. Regulatory roles of D-serine in NMDA receptor-mediated synaptic plasticity have been reported. Nonetheless, it is unclear whether and how neonatal deficits in NMDA-receptor-mediated neurotransmission affect adult brain functions and behavior. Likewise, the role of D-serine during development remains elusive. Here we report behavioral and electrophysiological deficits associated with the frontal cortex in Pick1 knockout mice, which show D-serine deficits in a neonatal- and forebrain-specific manner. The pathological manifestations observed in adult Pick1 mice are rescued by transient neonatal supplementation of D-serine, but not by a similar treatment in adulthood. These results indicate a role for D-serine in neurodevelopment and provide novel insights on how we interpret data of psychiatric genetics, indicating the involvement of genes associated with D-serine synthesis and degradation, as well as how we consider animal models with neonatal application of NMDA receptor antagonists.

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Acknowledgements

We thank Ms Yukiko Lema for organizing the figures and manuscript. This work was supported by USPHS grants MH-084018 (AS), MH-094268 Silvo O Conte center (AS), MH-069853 (AS), MH-085226 (AS), MH-088753 (AS), MH-092443 (AS), MH-091387 (AS), MH-057683 (PO), MH-083728 (MP), Stanley (AS), RUSK (AS), S-R foundations (AS), NARSAD (AS, PO and MP), the Maryland Stem Cell Research Fund (AS), MEXT KAKENHI (TT), JST CREST (TT) and the Naito and Uehara Memorial Foundations (JN).

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Author notes

  1. J Nomura

    Present address: 7Current address: Mental Biology, RIKEN Brain Science Institute and Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University.,

  2. P Nuñez-Abades

    Present address: 8Current address: Departamento de Fisiologia, Universidad de Sevilla, Spain.,

  3. P O'Donnell

    Present address: 9Current address: Psychiatry & Behavioral Disorders, Neuroscience Research Unit, Pfizer.,

Authors and Affiliations

  1. Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    J Nomura, H Jaaro-Peled, T Cash-Padgett, F Emiliani, M A Kondo, M A Landek-Salgado, Y Ayhan, A Kamiya, M Pletnikov & A Sawa

  2. Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA,

    E Lewis, P Nuñez-Abades, F Huppe-Gourgues & P O'Donnell

  3. Mental Biology, RIKEN Brain Science Institute, Wako, Japan

    A Furuya & T Takumi

  4. Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan

    T Takumi

  5. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    R Huganir, M Pletnikov & A Sawa

  6. Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA

    P O'Donnell

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Nomura, J., Jaaro-Peled, H., Lewis, E. et al. Role for neonatal D-serine signaling: prevention of physiological and behavioral deficits in adult Pick1 knockout mice. Mol Psychiatry 21, 386–393 (2016). https://doi.org/10.1038/mp.2015.61

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