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Alteration of intrinsic amounts of d-serine in the mice lacking serine racemase and d-amino acid oxidase

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Abstract

For elucidation of the regulation mechanisms of intrinsic amounts of d-serine (d-Ser) which modulates the neuro-transmission of N-methyl-d-aspartate receptors in the brain, mutant animals lacking serine racemase (SRR) and d-amino acid oxidase (DAO) were established, and the amounts of d-Ser in the tissues and physiological fluids were determined. d-Ser amounts in the frontal brain areas were drastically decreased followed by reduced SRR activity. On the other hand, a moderate but significant decrease in d-Ser amounts was observed in the cerebellum and spinal cord of SRR knock-out (SRR−/−) mice compared with those of control mice, although the amounts of d-Ser in these tissues were low. The amounts of d-Ser in the brain and serum were not altered with aging. To clarify the uptake of exogenous d-Ser into the brain tissues, we have determined the d-Ser of SRR−/− mice after oral administration of d-Ser for the first time, and a drastic increase in d-Ser amounts in all the tested tissues was observed. Because both DAO and SRR are present in some brain areas, we have established the double mutant mice lacking SRR and DAO for the first time, and the contribution of both enzymes to the intrinsic d-Ser amounts was investigated. In the frontal brain, most of the intrinsic d-Ser was biosynthesized by SRR. On the other hand, half of the d-Ser present in the hindbrain was derived from the biosynthesis by SRR. These results indicate that the regulation of intrinsic d-Ser amounts is different depending on the tissues and provide useful information for the development of treatments for neuronal diseases.

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Acknowledgments

We thank Dr. Tsuda, Dokkyo Medical University, for the preparation of Fig. 1. This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (K.H. 22390007 and R.K. 17500258) and the Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists (Y.M.). The authors thank Shiseido Co., Ltd., (Tokyo, Japan) for their technical support.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Yurika Miyoshi, Kyoko Ueno, Yosuke Tojo & Kenji Hamase

  2. Department of Pharmaceutical Sciences, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi, 324-8501, Japan

    Ryuichi Konno

  3. Department of Anatomy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Jumpei Sasabe & Sadakazu Aiso

  4. Innovative Science Research and Development Center, Shiseido Co., Ltd., 2-12-1 Fukuura, Kanazawa-ku, Yokohama, 236-8643, Japan

    Yosuke Tojo & Masashi Mita

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  1. Yurika Miyoshi
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  2. Ryuichi Konno
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  3. Jumpei Sasabe
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  4. Kyoko Ueno
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Correspondence to Kenji Hamase.

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Miyoshi, Y., Konno, R., Sasabe, J. et al. Alteration of intrinsic amounts of d-serine in the mice lacking serine racemase and d-amino acid oxidase. Amino Acids 43, 1919–1931 (2012). https://doi.org/10.1007/s00726-012-1398-4

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  • DOI: https://doi.org/10.1007/s00726-012-1398-4

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