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

• Project/Area Number: 18K06888
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: University 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: ¥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。

Research Products

• [Int'l Joint Research] Department of Biochemistry/TMSS Medical College & Hospital(バングラデシュ)
• [Journal Article] Generation and characterization of a Meflin-CreERT2 transgenic line for lineage tracing in white adipose tissue (2021)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice (2021)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characteristics of internalization of NMDA-type GluRs with antibodies to GluN1 and GluN2B (2020)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia (2020)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Visualization of activity-regulated BDNF expression in the living mouse brain using non-invasive near-infrared bioluminescence imaging (2020)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Vascular PDGFR-alpha protects against BBB dysfunction after stroke in mice (2020)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Oligodendrogenesis and Myelin Formation in the Forebrain Require Platelet-derived Growth Factor Receptor-alpha (2020)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structural insights into selective interaction between type IIa receptor protein tyrosine phosphatases and Liprin-α (2020)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced bioluminescent sensor for longitudinal detection of CREB activation in living cells (2019)
  • 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
  • Peer Reviewed
• [Journal Article] A new bioluminescence-based tool for modulating target proteins in live cells (2019)
  • Author(s): Ishimoto Tetsuya、Mori Hisashi
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 18239-18239
  • DOI: 10.1038/s41598-019-54712-y
  • Peer Reviewed / Open Access
• [Journal Article] Screening inducers of neuronal BDNF gene transcription using primary cortical cell cultures from BDNF-luciferase transgenic mice (2019)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Powerful Homeostatic Control of Oligodendroglial Lineage by PDGFRα in Adult Brain (2019)
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
• [Presentation] Gastrin-releasing Peptide Neurons in the Suprachiasmatic Nucleus Play an Essential Role in Behavioral Circadian Rhysm (2020)
  • Author(s): Ruth Li, Arisa Hirano, Takeshi Sakurai, Hisashi Mori, Ran Inoue
  • Organizer: 第43回日本神経科学大会
  • Int'l Joint Research
• [Presentation] Both D-serine siganling and hippocampal neurogenesis are required for maintaining remote contextual fear memory following repeated memory retrievals (2020)
  • Author(s): Xiance Ni, Ran Inoue, Hisashi Mori
  • Organizer: 第43回日本神経科学大会
  • Int'l Joint Research
• [Presentation] Microexon splicing of Ptprd gene controls locomotor activity and social behavior (2020)
  • 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
  • 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
• [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
• [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
  • 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
• [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
• [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
  • 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
  • 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
• [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
• [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
• [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
• [Remarks] 富山大学分子神経科学講座
  • URL: http://www.med.u-toyama.ac.jp/molneurosci/index.html