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Analysis of D-serine dynamics for the development of new drug against neuropsychiatric disorders

Research Project

Project/Area Number 18K06888
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 48030:Pharmacology-related
Research InstitutionUniversity of Toyama

Principal Investigator

Mori Hisashi  富山大学, 学術研究部医学系, 教授 (00239617)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywordsセリンラセマーゼ / D-セリン / NMDA受容体 / セリンシャトル仮説 / 遺伝子発現制御 / トランスジェニックマウス
Outline of Final Research Achievements

In the mammalian brain, L-serine produced in astrocytes is transported to neurons and changes into D-serine by serine racemase (SRR). D-Serine returns to astrocyte, and this process is hypothesized as “serine shuttle” based on the in vitro experiments. However, this hypothesis is not examined in vivo. In this study, we generated novel two transgenic mouse strains inducing the D-serine degradation in astrocytes- or neurons-specific manner. Both transgenic mouse strains showed significant reduction of D-serine in the brain, suggesting the novel mechanism of D-serine transport from astrocytes to neurons. Furthermore, we generated another novel mouse strain detecting SRR gene expression with bioluminescence in vivo. Using this mouse strain, we identified some compounds affecting the gene expression of SRR.

Academic Significance and Societal Importance of the Research Achievements

神経伝達、神経可塑性、高次脳機能、神経精神疾患に関わるNMDA型グルタミン酸受容体は、内在性のD-セリンによって活性制御を受ける。脳内のD-セリン動態機構は十分には明らかされていない。本研究では、新たな遺伝子組換えマウス系統を作製して解析し、D-セリンがアストロサイトから神経細胞に輸送され細胞間で分布の平衡を保つ機構の存在が示唆された。またD-セリン合成を担うセリン異性化酵素の遺伝子発現を生体発光で計測できるマウス系統の作製にも初めて成功した。本研究成果には、D-セリン動態を明らかにする学術的意義の他に、D-セリン操作を介し神経精神疾患への新たな治療薬の開発につながる社会的意義がある。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (37 results)

All 2021 2020 2019 2018 Other

All Int'l Joint Research (1 results) Journal Article (20 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 20 results,  Open Access: 18 results) Presentation (12 results) (of which Int'l Joint Research: 5 results,  Invited: 1 results) Book (2 results) Remarks (2 results)

  • [Int'l Joint Research] Department of Biochemistry/TMSS Medical College & Hospital(バングラデシュ)

    • Related Report
      2018 Research-status Report
  • [Journal Article] Generation and characterization of a Meflin-CreERT2 transgenic line for lineage tracing in white adipose tissue2021

    • Author(s)
      Kuwano Takahide, Izumi Hironori, Aslam Muhammad Rahil, Igarashi Yoshiko, Bilal Muhammad, Nishimura Ayumi, Watanabe Yoshiyuki, Nawaz Allah, Kado Tomonobu, Ikuta Koichi, Yamamoto Seiji, Sasahara Masakiyo, Fujisaka Shiho, Yagi Kunimasa, Mori Hisashi, Tobe Kazuyuki
    • Journal Title

      PLOS ONE

      Volume: 16 Issue: 3 Pages: e0248267-e0248267

    • DOI

      10.1371/journal.pone.0248267

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice2021

    • Author(s)
      Yoshida T, Yamagata A, Imai A, Kim J, Izumi H, Nakashima S, Shiroshima T, Maeda A, Iwasawa-Okamoto S, Azechi K, Osaka F, Saitoh T, Maenaka K, Shimada T, Fukata Y, Fukata M, Matsumoto J, Nishijo H, Takao K, Tanaka S, Okabe S, Tabuchi K, Uemura T, Mishina M, Mori H & Fukai S
    • Journal Title

      Nature Communications

      Volume: 12(1) Issue: 1 Pages: 1848-1848

    • DOI

      10.1038/s41467-021-22059-6

    • NAID

      120006996978

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Characteristics of internalization of NMDA-type GluRs with antibodies to GluN1 and GluN2B2020

    • Author(s)
      Yukitoshi Takahashi, Shigeko Nishimura, Emiko Takao, Risa Kasai, Kaoru Enokida, Kuniko Ida, Masataka Fukuoka, Takayoshi Koike, Hiroo Omatsu, Tokito Yamaguchi, Shiho Takano, Tomoyuki Yoshida, Hisashi Mori
    • Journal Title

      Journal of Neuroimmunology

      Volume: 349 Pages: 577427-577427

    • DOI

      10.1016/j.jneuroim.2020.577427

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia2020

    • Author(s)
      Ishizuka Kanako、Yoshida Tomoyuki、Kawabata Takeshi、Imai Ayako、Mori Hisashi、Kimura Hiroki、Inada Toshiya、Okahisa Yuko、Egawa Jun、Usami Masahide、Kushima Itaru、Morikawa Mako、Okada Takashi、Ikeda Masashi、Branko Aleksic、Mori Daisuke、Someya Toshiyuki、Iwata Nakao、Ozaki Norio
    • Journal Title

      Journal of Neurodevelopmental Disorders

      Volume: 12 Issue: 1 Pages: 25-25

    • DOI

      10.1186/s11689-020-09325-2

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Visualization of activity-regulated BDNF expression in the living mouse brain using non-invasive near-infrared bioluminescence imaging2020

    • Author(s)
      Fukuchi Mamoru、Saito Ryohei、Maki Shojiro、Hagiwara Nami、Nakajima Yumena、Mitazaki Satoru、Izumi Hironori、Mori Hisashi
    • Journal Title

      Molecular Brain

      Volume: 13 Issue: 1 Pages: 122-122

    • DOI

      10.1186/s13041-020-00665-7

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Vascular PDGFR-alpha protects against BBB dysfunction after stroke in mice2020

    • Author(s)
      Nguyen Quang Linh、Okuno Noriko、Hamashima Takeru、Dang Son Tung、Fujikawa Miwa、Ishii Yoko、Enomoto Atsushi、Maki Takakuni、Nguyen Hoang Ngoc、Nguyen Van Tuyen、Fujimori Toshihiko、Mori Hisashi、Andrae Johanna、Betsholtz Christer、Takao Keizo、Yamamoto Seiji、Sasahara Masakiyo
    • Journal Title

      Angiogenesis

      Volume: 24 Issue: 1 Pages: 35-46

    • DOI

      10.1007/s10456-020-09742-w

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Oligodendrogenesis and Myelin Formation in the Forebrain Require Platelet-derived Growth Factor Receptor-alpha2020

    • Author(s)
      Hamashima Takeru、Ishii Yoko、Nguyen Linh Quang、Okuno Noriko、Sang Yang、Matsushima Takako、Kurashige Yoichi、Takebayashi Hirohide、Mori Hisashi、Fujimori Toshihiko、Yamamoto Seiji、Sasahara Masakiyo
    • Journal Title

      Neuroscience

      Volume: 436 Pages: 11-26

    • DOI

      10.1016/j.neuroscience.2020.04.001

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Structural insights into selective interaction between type IIa receptor protein tyrosine phosphatases and Liprin-α2020

    • Author(s)
      Wakita Maiko、Yamagata Atsushi、Shiroshima Tomoko、Izumi Hironori、Maeda Asami、Sendo Mizuki、Imai Ayako、Kubota Keiko、Goto-Ito Sakurako、Sato Yusuke、Mori Hisashi、Yoshida Tomoyuki、Fukai Shuya
    • Journal Title

      Nature Communications

      Volume: 11 Issue: 1 Pages: 649-649

    • DOI

      10.1038/s41467-020-14516-5

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Enhanced bioluminescent sensor for longitudinal detection of CREB activation in living cells2019

    • Author(s)
      Noda Natsumi、Ishimoto Tetsuya、Mori Hisashi、Ozawa Takeaki
    • Journal Title

      Photochemical & Photobiological Sciences

      Volume: 18 Issue: 11 Pages: 2740-2747

    • DOI

      10.1039/c9pp00249a

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] A new bioluminescence-based tool for modulating target proteins in live cells2019

    • Author(s)
      Ishimoto Tetsuya、Mori Hisashi
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 18239-18239

    • DOI

      10.1038/s41598-019-54712-y

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Screening inducers of neuronal BDNF gene transcription using primary cortical cell cultures from BDNF-luciferase transgenic mice2019

    • Author(s)
      Fukuchi Mamoru、Okuno Yui、Nakayama Hironori、Nakano Aoi、Mori Hisashi、Mitazaki Satoru、Nakano Yuka、Toume Kazufumi、Jo Michiko、Takasaki Ichiro、Watanabe Kazuki、Shibahara Naotoshi、Komatsu Katsuko、Tabuchi Akiko、Tsuda Masaaki
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 11833-11833

    • DOI

      10.1038/s41598-019-48361-4

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Powerful Homeostatic Control of Oligodendroglial Lineage by PDGFRα in Adult Brain2019

    • Author(s)
      Dang Thanh Chung、Ishii Yoko、Nguyen Van De、Yamamoto Seiji、Hamashima Takeru、Okuno Noriko、Nguyen Quang Linh、Sang Yang、Ohkawa Noriaki、Saitoh Yoshito、Shehata Mohammad、Takakura Nobuyuki、Fujimori Toshihiko、Inokuchi Kaoru、Mori Hisashi、Andrae Johanna、Betsholtz Christer、Sasahara Masakiyo
    • Journal Title

      Cell Reports

      Volume: 27 Issue: 4 Pages: 1073-1089.e5

    • DOI

      10.1016/j.celrep.2019.03.084

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Bioluminescence imaging of Arc expression in mouse brain under acute and chronic exposure to pesticides.2019

    • Author(s)
      Izumi, H., Ishimoto, T., Yamamoto, H., Mori, H.
    • Journal Title

      Neurotoxicology

      Volume: 71 Pages: 52-59

    • DOI

      10.1016/j.neuro.2018.12.003

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Serine racemase deletion attenuates neurodegeneration and microvascular damage in diabetic retinopathy.2018

    • Author(s)
      Ozaki H, Inoue R, Matsushima T, Sasahara M, Hayashi A, Mori H.
    • Journal Title

      PLoS One

      Volume: 13 Issue: 1 Pages: e0190864-e0190864

    • DOI

      10.1371/journal.pone.0190864

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Design, synthesis, and evaluation of novel inhibitors for wild-type human serine racemase.2018

    • Author(s)
      Takahara S, Nakagawa K, Uchiyama T, Yoshida T, Matsumoto K, Kawasumi Y, Mizuguchi M, Obita T, Watanabe Y, Hayakawa D, Gouda H, Mori H, Toyooka N.
    • Journal Title

      Bioorg Med Chem Lett.

      Volume: 28 Issue: 3 Pages: 441-445

    • DOI

      10.1016/j.bmcl.2017.12.021

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impairment in extinction of cued fear memory in syntenin-1 knockout mice.2018

    • Author(s)
      Talukdar G, Inoue R, Yoshida T, Mori H.
    • Journal Title

      Neurobiol Learn Mem

      Volume: 149 Pages: 58-67

    • DOI

      10.1016/j.nlm.2018.01.006

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Dissociated role of D-serine in extinction during consolidation vs. reconsolidation of context conditioned fear.2018

    • Author(s)
      Inoue R, Talukdar G, Takao K, Miyakawa T, Mori H.
    • Journal Title

      Front Mol Neurosci.

      Volume: 11 Pages: 161-161

    • DOI

      10.3389/fnmol.2018.00161

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inflammatory cytokine-mediated induction of serine racemase in atopic dermatitis.2018

    • Author(s)
      Yoshihisa Y, Rehman MU, Nakagawa M, Matsukuma S, Makino T, Mori H, Shimizu T.
    • Journal Title

      J Cell Mol Med

      Volume: ー Issue: 6 Pages: 3133-3138

    • DOI

      10.1111/jcmm.13592

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Deletion of serine racemase confers D-serine -dependent resilience to chronic social defeat stress.2018

    • Author(s)
      Dong C, Zhang JC, Ren Q, Ma M, Qu Y, Zhang K, Yao W, Ishima T, Mori H, Hashimoto K.
    • Journal Title

      Neurochem Int.

      Volume: 116 Pages: 43-51

    • DOI

      10.1016/j.neuint.2018.03.008

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Glucocorticoid receptor-mediated amygdalar metaplasticity underlies adaptive modulation of fear memory by stress.2018

    • Author(s)
      Inoue R, Abdou K, Hayashi-Tanaka A, Muramatsu SI, Mino K, Inokuchi K, Mori H.
    • Journal Title

      eLife

      Volume: 7

    • DOI

      10.7554/elife.34135

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 大脳皮質神経細胞の電気刺激によるPtpd遺伝子の微小エクソン選択調節2020

    • Author(s)
      出村 舞奈, 今井 彩子, 田端 俊英, 森 寿, 吉田 知之
    • Organizer
      日本生化学会北陸支部第38回大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Gastrin-releasing Peptide Neurons in the Suprachiasmatic Nucleus Play an Essential Role in Behavioral Circadian Rhysm2020

    • Author(s)
      Ruth Li, Arisa Hirano, Takeshi Sakurai, Hisashi Mori, Ran Inoue
    • Organizer
      第43回日本神経科学大会
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Both D-serine siganling and hippocampal neurogenesis are required for maintaining remote contextual fear memory following repeated memory retrievals2020

    • Author(s)
      Xiance Ni, Ran Inoue, Hisashi Mori
    • Organizer
      第43回日本神経科学大会
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Microexon splicing of Ptprd gene controls locomotor activity and social behavior2020

    • Author(s)
      Ayako Tabata-Imai, Mizuki Sendo, Hironori Izumi, Keizo Takao, Hisashi Mori, Tomoyuki Yoshida
    • Organizer
      第43回日本神経科学大会
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 大脳皮質神経細胞の電気刺激によるPtprd遺伝子微小エクソンの選択的スプライシング調節2020

    • Author(s)
      出村 舞奈, 今井 彩子, 田端 俊英, 森 寿, 吉田 知之
    • Organizer
      第67回中部日本生理学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] D-serineは脊索動物ホヤの変態時に表皮細胞からの細胞外基質の分泌を制御する2020

    • Author(s)
      Krasovec Gabriel, 保住 暁子, 吉田 知之, 濱田 麻友子, 白石 慧, 佐竹 炎, 堀江 健生, 森 寿, 笹倉 靖徳
    • Organizer
      第43回日本分子生物学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Durable fear memory after repeated memory retreaval requires D-serine and intact adult hipocampal neurogenesis.2019

    • Author(s)
      Inoue R, Ni X, Mori H.
    • Organizer
      IDAR2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Erasure of remote contextual fear memory by blocking both D-serine signaling pathway and adult hippocampal neurogenesis.2019

    • Author(s)
      Inoue R, Ni X, Mori H.
    • Organizer
      第49回日本神経精神薬理学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] 発光蛋白質を用いた新しい細胞内蛋白質機能操作法2019

    • Author(s)
      石本哲也、森寿
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] 遺伝子操作マウスを用いたセリンラセマーゼとD-セリンの機能解析2018

    • Author(s)
      森 寿
    • Organizer
      D-アミノ酸学会第3回ワークショップ
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] The opposite role of D-serine in immediate and retrieval extinction of contextual fear memory.2018

    • Author(s)
      Mori H.
    • Organizer
      The 18th World Congress of Basic and Clinical Pharmacology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 恐怖記憶の消去における脳内D-セリンの役割2018

    • Author(s)
      井上 蘭, Talukdar Gourango, 森 寿
    • Organizer
      第14回D-アミノ酸学会学術講演会
    • Related Report
      2018 Research-status Report
  • [Book] Ketamine; From Abused Drug to Rapid-Acting Antidepressant.2020

    • Author(s)
      Mori, H. Site of ketamine action on the NMDA receptor. (p47-67)
    • Total Pages
      189
    • Publisher
      Springer
    • ISBN
      9789811529016
    • Related Report
      2019 Research-status Report
  • [Book] 脳神経化学、 5章「興奮性神経伝達物質とそれらの受容体のダイナミクス」p44-54.2018

    • Author(s)
      井上蘭、森寿
    • Total Pages
      368
    • Publisher
      化学同人
    • ISBN
      4759817263
    • Related Report
      2018 Research-status Report
  • [Remarks] 富山大学学術研究部医学系 医学部 分子神経科学講座

    • URL

      http://www.med.u-toyama.ac.jp/molneurosci/index.html

    • Related Report
      2020 Annual Research Report
  • [Remarks] 富山大学分子神経科学講座

    • URL

      http://www.med.u-toyama.ac.jp/molneurosci/index.html

    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2022-01-27  

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