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Elucidation of functional roles of two GABA synthetic enzyme isoforms using knockout rats

Research Project

Project/Area Number 19K06881
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 46010:Neuroscience-general-related
Research InstitutionGunma University

Principal Investigator

Yanagawa Yuchio  群馬大学, 大学院医学系研究科, 客員教授 (90202366)

Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsGABA / グルタミン酸脱炭酸酵素 / GAD65 / GAD67 / ノックアウトラット
Outline of Research at the Start

GABAは主要な神経伝達物質であり、グルタミン酸脱炭酸酵素(GAD; GAD65とGAD67の2型存在)によって合成される。GAD65とGAD67は、分子量、補酵素との親和性、細胞内局在などで違いがあり、異なる遺伝子にコードされている。GADやGABAは統合失調症、てんかん、不安症、抗GAD抗体関連脳症など様々な精神神経疾患に関与することが報告されている。
本研究では主にノックアウトラットを作製・解析することにより、脳機能におけるGAD65分子とGAD67分子の役割を明らかにし、同時にGAD及びGABAが関与する精神神経疾患の分子病態や病態生理の解明に貢献する。

Outline of Final Research Achievements

GABA is a major neurotransmitter in the mammalian central nervous system. It is synthesized from glutamate by glutamate decarboxylase (GAD). Two isoforms of GAD, GAD65 and GAD67 are separately encoded by the Gad2 and Gad1 genes, respectively. We generated Gad1/Gad2 mutant rats of various genotypes and characterized their phenotypes. For example, the extremely low GABA content in Gad1/Gad2 double knockout (DKO) rat forebrains at embryonic day 20 indicated that almost all GABA is synthesized by GADs. In addition, the number of neural progenitor cells was low in the DKO rat cerebral cortex at the embryonic stage, suggesting that GABA is critical for neural development. These KO rats will be a useful tool for clarifying the role of GADs and GABA in the brain.

Academic Significance and Societal Importance of the Research Achievements

GABAは代表的な神経伝達物質であり、グルタミン酸脱炭酸酵素(GAD;GAD65とGAD67の2型存在)により合成される。GADやGABAは、多くの精神神経疾患に関与している。例えば、GAD67をコードするGAD1遺伝子の機能喪失変異と統合失調症、発達性およびてんかん性脳症との関連が報告されている。我々の作製したGadノックアウトラットでは、様々な表現型が見出された。これらのGadノックアウトラットは、脳におけるGADの役割の解明だけでなくヒト精神神経疾患の病態の解明に役立つことが期待される。

Report

(5 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (29 results)

All 2023 2022 2021 2020 2019 Other

All Int'l Joint Research (4 results) Journal Article (11 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 10 results,  Open Access: 9 results) Presentation (13 results) (of which Invited: 2 results) Remarks (1 results)

  • [Int'l Joint Research] Otto-von-Guericke University Magdeburg(ドイツ)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] The University of Queensland(オーストラリア)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] Otto-von-Guericke University Magdeburg(ドイツ)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] The University of Queensland(オーストラリア)

    • Related Report
      2019 Research-status Report
  • [Journal Article] Impact of GAD65 and/or GAD67 deficiency on perinatal development in rats.2022

    • Author(s)
      Jiang W, Kakizaki T, Fujihara K, Miyata S, Zhang Y, Suto T, Kato D, Saito S, Shibasaki K, Ishizaki Y, Isoda K, Yokoo H, Obinata H, Hirano T, Miyasaka Y, Mashimo T, Yanagawa Y.
    • Journal Title

      .FASEB J .

      Volume: 36(2) Issue: 2

    • DOI

      10.1096/fj.202101389r

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ノックアウトラットによる2種類のGABA合成酵素アイソフォームの機能的役割の解明2021

    • Author(s)
      藤原和之、柿崎利和、Weiru Jiang、宮田茂雄、柳川右千夫
    • Journal Title

      細胞

      Volume: 53 Pages: 443-447

    • NAID

      40022633114

    • Related Report
      2021 Research-status Report
  • [Journal Article] Rats deficient in the GAD65 isoform exhibit epilepsy and premature lethality.2021

    • Author(s)
      Kakizaki T, Ohshiro T, Itakura M, Konno K, Watanabe M, Mushiake H, Yanagawa Y.
    • Journal Title

      FASEB J.

      Volume: 35 Issue: 2 Pages: 1-15

    • DOI

      10.1096/fj.202001935r

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Genetic Deletion of Glutamate Decarboxylase 67-kDa Isoform Alters Conditioned Fear Behavior in Rats.2021

    • Author(s)
      Fujihara K, Sato T, Miyasaka Y, Mashimo T, Yanagawa Y.
    • Journal Title

      FEBS Open Bio.

      Volume: 11 Issue: 2 Pages: 340-353

    • DOI

      10.1002/2211-5463.13065

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Global knockdown of glutamate decarboxylase 67 elicits emotional abnormality in mice.2021

    • Author(s)
      Miyata S, Kakizaki T, Fujihara K, Obinata H, Hirano T, Nakai J, Tanaka M, Itohara S, Watanabe M, Tanaka KF, Abe M, Sakimura K, Yanagawa Y.
    • Journal Title

      Mol Brain

      Volume: 14 Issue: 1 Pages: 5-5

    • DOI

      10.1186/s13041-020-00713-2

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Behavioral consequences of a combination of Gad1 haplodeficiency and adolescent exposure to NMDA receptor antagonist in Long-Evans rat.2021

    • Author(s)
      Fujihara K, Sato T, Higeta K, Miyasaka Y, Mashimo T, Yanagawa Y.
    • Journal Title

      Front Pharmacol.

      Volume: 12 Pages: 646088-646088

    • DOI

      10.3389/fphar.2021.646088

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] CRISPR/Cas9-engineered Gad1 elimination in rats leads to complex behavioral changes: implications for schizophrenia2020

    • Author(s)
      Fujihara Kazuyuki、Yamada Kazuo、Ichitani Yukio、Kakizaki Toshikazu、Jiang Weiru、Miyata Shigeo、Suto Takashi、Kato Daiki、Saito Shigeru、Watanabe Masahiko、Kajita Yuki、Ohshiro Tomokazu、Mushiake Hajime、Miyasaka Yoshiki、Mashimo Tomoji、Yasuda Hiroki、Yanagawa Yuchio
    • Journal Title

      Translational Psychiatry

      Volume: 10 Issue: 1 Pages: 426-426

    • DOI

      10.1038/s41398-020-01108-6

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hyper-formation of GABA and glycine co-releasing terminals in the mouse cerebellar nuclei after deprivation of GABAergic inputs from Purkinje cells.2020

    • Author(s)
      Kobayashi S, Kim J, Yanagawa Y, Suzuki N, Saito H, Takayama C.
    • Journal Title

      Neuroscience

      Volume: 426 Pages: 88-100

    • DOI

      10.1016/j.neuroscience.2019.11.030

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] GABA in the suprachiasmatic nucleus refines circadian output rhythms in mice.2019

    • Author(s)
      Ono D, Honma KI, Yanagawa Y, Yamanaka A, Honma S
    • Journal Title

      Commun Biol.

      Volume: 2 Issue: 1 Pages: 232-232

    • DOI

      10.1038/s42003-019-0483-6

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Loss of glutamate decarboxylase 67 in somatostatin-expressing neurons leads to anxiety-like behavior and alteration in the Akt/GSK3beta signaling.2019

    • Author(s)
      Miyata S, Kumagaya R, Kakizaki T, Fujihara K, Wakamatsu K, Yanagawa Y.
    • Journal Title

      Front Behav Neurosci.

      Volume: 13 Pages: 131-131

    • DOI

      10.3389/fnbeh.2019.00131

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Store-Operated Calcium Channels Are Involved in Spontaneous Slow Calcium Oscillations in Striatal Neurons2019

    • Author(s)
      Kikuta Satomi、Iguchi Yoshio、Kakizaki Toshikazu、Kobayashi Kazuto、Yanagawa Yuchio、Takada Masahiko、Osanai Makoto
    • Journal Title

      Frontiers in Cellular Neuroscience

      Volume: 13 Pages: 1-9

    • DOI

      10.3389/fncel.2019.00547

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] グルタミン酸脱炭酸酵素67kDaアイソフォームの欠損はラットにおいて物体位置再認を障害する。2023

    • Author(s)
      藤原和之、柿崎利和、柳川右千夫
    • Organizer
      日本生理学会第100回記念大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Gad2ノックアウトラット脳におけるGAD67の細胞内局在2022

    • Author(s)
      柿崎利和、柳川右千夫
    • Organizer
      第45回日本神経科学大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] GABA合成酵素の遺伝子機能探索:マウスとラットのノックアウト動物を利用した比較研究2022

    • Author(s)
      柳川右千夫
    • Organizer
      先端モデル動物支援プラットフォーム2021年度成果発表会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] GABAニューロン研究のための遺伝子改変ラット2022

    • Author(s)
      柳川右千夫
    • Organizer
      第15回 ラットリソース・リサーチ研究会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] Neonatal NMDA receptor blockade and glutamate decarboxylase 67-kDa isoform haplodeficiency synergistically cause behavioral alterations2021

    • Author(s)
      Fujihara K, Kakizaki T, Yanagawa Y.
    • Organizer
      第44回日本神経科学大会
    • Related Report
      2021 Research-status Report
  • [Presentation] Behavioral analysis of GAD65 knockout rats2021

    • Author(s)
      Kakizaki T, Fujihara K, Yanagawa Y.
    • Organizer
      第44回日本神経科学大会
    • Related Report
      2021 Research-status Report
  • [Presentation] The effect of GABA deficiency on embryonic neocortical development2021

    • Author(s)
      Jiang W, Kakizaki T, Miyoshi G, Yanagawa Y.
    • Organizer
      第44回日本神経科学大会
    • Related Report
      2021 Research-status Report
  • [Presentation] The effect of GABA on embryonic neocortical development2021

    • Author(s)
      Jiang W, Kakizaki T, Miyoshi G, Kurachi M, Ishizaki Y, Yanagawa Y.
    • Organizer
      第68回北関東医学会
    • Related Report
      2021 Research-status Report
  • [Presentation] GABA合成酵素GAD67ハプロ不全と新生仔期NMDA型グルタミン酸受容体遮断の組み合わせにより生じる行動学的表現型2020

    • Author(s)
      藤原和之、佐藤匠、宮坂佳樹、真下知士、柳川右千夫
    • Organizer
      NPBPPP2020合同年会
    • Related Report
      2020 Research-status Report
  • [Presentation] The role of GABA in embryonic cortical development.2020

    • Author(s)
      Weiru Jiang, Toshikazu Kakizaki, Goichi Miyoshi, Yuchio Yanagawa
    • Organizer
      第67回北関東医学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] GAD65/67二重変異ラットの表現型解析2019

    • Author(s)
      Weiru Jiang、柿崎利和、藤原和之、宮田茂雄、張月、須藤貴史、加藤大樹、齋藤繁、柴崎貢志、石崎泰樹、宮坂佳樹、真下知士、柳川右千夫
    • Organizer
      日本ゲノム編集学会第4回大会
    • Related Report
      2019 Research-status Report
  • [Presentation] GAD65欠損ラットは脳内GABA含量の減少とてんかん重積状態を示す2019

    • Author(s)
      柿崎利和、Weiru Jiang、須藤貴史、齋藤繁、板倉誠、渡辺雅彦、柳川右千夫
    • Organizer
      第42回日本神経科学大会、第62回日本神経化学会大会
    • Related Report
      2019 Research-status Report
  • [Presentation] Roles of rat glutamate decarboxylase isoforms in the perinatal period2019

    • Author(s)
      Weiru Jiang, Toshikazu Kakizaki, Kazuyuki Fujihara, Shigeo Miyata, Yue Zhang, Takashi Suto, Daiki Kato, Shigeru Saito, Koji Shibasaki, Yasuki Ishizaki, Yoshiki Miyasaka, Tomoji Mashimo, Yuchio Yanagawa
    • Organizer
      第42回日本神経科学大会、第62回日本神経化学会大会
    • Related Report
      2019 Research-status Report
  • [Remarks] 群馬大学 大学院医学系研究科 医学部 医学科 大学院医学系研究科 医科学専攻 組織 遺伝発達行動学

    • URL

      http://www.med.gunma-u.ac.jp/med-organization/neurosci/neurosci-development/106.html

    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2024-01-30  

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