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Functional analysis of the molecular mechanism of synaptic plasticity using conditional gene targeting

Research Project

Project/Area Number 10480226
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section一般
Research Field Neuroscience in general
Research InstitutionNIIGATA UNIVERSITY

Principal Investigator

SAKIMURA Kenji  Brain Research institute, Niigata University, Department of Cellular Neurobiology, Professor, 脳研究科, 教授 (40162325)

Co-Investigator(Kenkyū-buntansha) 森田 貴雄  新潟大学, 脳研究所, 講師(研究機関研究員)
Project Period (FY) 1998 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥12,100,000 (Direct Cost: ¥12,100,000)
Fiscal Year 2000: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 1999: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1998: ¥4,800,000 (Direct Cost: ¥4,800,000)
KeywordsConditional targeting / C57BL / 6 / Cre recombinase / ES cells / Synaptic plasticity / Purkinje cell / シナプス肥厚 / PSD / PSD95 / SAP90 / AMPA受容体チャネル / GRIP-I / PDZドメイン / NMDA受容体チャネル / GRIP
Research Abstract

Gene targeting is a useful method for the analyses of molecular functions in vivo. However in the interpretation of the results of knockout mouse studies, there are two problems. One is that the gene disruption occurs in the whole body, but not in the restricted region. Secondly, since the gene expression starts early in development, gene targeting results in developmental defects and compensatory regulation of other genes. Because of these problems, it has been difficult to precisely determine the role of the molecules in mediating synaptic plasticity and leaning in the mature brain.
Recently, a spatio-temporally restricted gene targeting system was developed. This method is based on the P1 phage Cre/loxP recombination system, where the Cre gene and a mutated ligand binding domain of the human progesterone receptor gene were fused to produce the CrePR gene. The recombinase activity of the CrePR protein is induced by the synthetic steroid, RU486, but not by endogenous hormones. By generating mutant mice in which the CrePR gene is expressed in a region-specific or cell-type specific manner, it has become feasible to achieve spatially and temporally regulated gene targeting.
We have established a mouse line which can be used to mediate inducible gene recombination specifically in cerebellar Purkinje cells. In the generated mutant mice (D2CPR), the CrePR gene is specifically expressed in Purkinje cells under the control of the GluRδ2 gene promoter. The GluRδ2 gene is abundantly and specifically expressed in the Purkinje cells. When these mice were crossed with a reporter mouse line carrying the lacZ reporter gene under a universally active promoter, CrePR-mediated expression of β-galactosidase was induced specifically in the mature Purkinje cells by the artificial progesterone receptor ligand RU486.

Report

(4 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (64 results)

All Other

All Publications (64 results)

  • [Publications] Kitayama,K.: "Purkinje cell specific and inducible gene recombination system generated from C57BL/6 mouse ES cells"Biochem.Biophys.Res.Commun.. (in press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ito,I.: "Input-specific targeting of NMDA receptor subtypes at mouse hippocampal CA3 pyramidal neuron synapses"Neuropharmacology. 39(6). 943-951 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Minami,T.: "Characterization of nociceptin/orphanin FQ-induced pain responses in conscious mice"Neuroscience. 97(1). 133-142 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yamakura,T.: " N-methyl-D-aspartate receptor channel block by meperidine is dependent on extracellular pH"Anesthesia and Analgesia. 90(4). 928-932 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tanaka,J.: "Gq protein α subunits Gαq and Gα11 are localized at postsynaptic extra-junctional membrane of cerebellar Purkinje cells and hippocampal pyramidal cells"Eur.J.Neurosci.. 12(3). 781-792 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Minami,T: "Involvement of primary afferent C-fibres in touch-evoked pain (allodynia) induced by prostaglandin E_2"Eur.J.Neurosci.. 11(6). 1849-1856 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hashimoto,K.: "Impairment of AMPA receptor function in cerebellar granule cells of ataxic mutant mouse stargazer"J.Neurosci.. 19(14). 6027-6036 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yamakura,T.: "Direct inhibition of the N-methyl-D-aspartate receptor channel by high concentrations of opioids"Anesthesiology. 91(4). 1053-1063 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Watanabe,M.: "Selective scarcity of NMDA receptor channel subunits in the stratum lucidum of the mouse hippocampal CA3"Eur.J.Neurosci.. 10(2). 478-487 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kiyama,Y.: "Increased thresholds for long-term potentiation and contextual learning in mice lacking NMDA-type receptor"J.Neurosci.. 18(17). 6704-6712 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mori,H.: "Role of the carboxy-terminal region of the GluRε2 subunit in synaptic localization of NMDA receptor channel"Neuron. 21(3). 571-580 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yamakura,T.: "Sensitivity of the NMDA receptor channel to butyrophenones is dependent on the ε2 subunit"Neuropharmacology. 37(6). 709-717 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ito,I.: "Distribution and development of NMDA receptor activities at hippocampal synapses"Neurosci.Res.. 30(2). 119-123 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 崎村建司: "発生工学の脳研究への応用"細胞工学. 17(10). 1605-1607 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 日本遺伝子治療学会 編: "遺伝子治療開発研究ハンドブック"(株)エヌ.ティー.エス. 1061 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 久野宗 監修: "細胞工学別冊「脳を知る」"(株)秀潤社. 205 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 真鍋俊也 編: "無敵のバイオテクニカルシリーズ特別編「脳・神経研究の進めかた」"(株)羊土社. 188 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kitayama, K.et al.: "Purkinje cell specific and inducible gene recombination system generated from C57BL/6 mouse ES cells"Biochem.Biophys.Res.Commun.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ito, I.et al.: "Input-specific targeting of NMDA receptor subtypes at mouse hippocampal CA3 pyramidal neuron synapses"Neuropharmacology. 39(6). 943-951 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Minami, T.et al.: "Characterization of nociceptin/orphanin FQ-induced pain responses in conscious mice"Neuroscience. 97(1). 133-142 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yamakura, T.et al.: "N-methyl-D-aspartate receptor channel block by meperidine is dependent on extracellular pH"Anesth.Analg.. 90(4). 928-932 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tanaka, J.et al.: "Gq protein α subunits Gαq and Gα11 are localized at postsynaptic extra-junctional membrane of cerebellar Purkinje cells and hippocampal pyramidal cells"Eur.J.Neurosci.. 12(3). 781-792 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Minami, T.et al.: "Involvement of primary afferent C-fibres in touch-evoked pain (allodynia) induced by prostaglandin E_2"Eur.J.Neurosci.. 11(6). 1849-1856 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hashimoto, K.et al.: "Impairment of AMPA receptor function in cerebellar granule cells of ataxic mutant mouse stargazer"J.Neurosci.. 19(14). 6027-6036 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yamakura, T.et al.: "Direct inhibition of the N-methyl-D-aspartate receptor channel by high concentrations of opioids"Anesthesiology. 91(4). 1053-1063 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Watanabe, M.et al.: "Selective scarcity of NMDA receptor channel subunits in the stratum lucidum of the mouse hippocampal CA3"Eur.J.Neurosci.. 10(2). 478-487 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kiyama, Y.et al.: "Increased thresholds for long-term potentiation and contextual learning in mice lacking NMDA-type receptor"J.Neurosci.. 18(17). 6704-6712 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mori, H.et al.: "Role of the carboxy-terminal region of the GluRε2 subunit in synaptic localization of NMDA receptor channel"Neuron. 21(3). 571-580 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ito, I.et al.: "Distribution and development of NMDA receptor activities at hippocampal synapses"Neurosci.Res.. 30(2). 119-123 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yamakura, T.et al.: "Sensitivity of the NMDA receptor channel to butyrophenones is dependent on the ε2 subunit"Neuropharmacology. 37(6). 709-717 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kitayama,K.: "Purkinje cell specific and inducible gene recombination system generated from C57BL/6 mouse ES cells"Biochem.Biophys.Res.Commun.. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ito,I.: "Input-specific targeting of NMDA receptor subtypes at mouse hippocampal CA3 pyramidal neuron synapses"Neuropharmacology. 39(6). 943-951 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Minami,T.: "Characterization of nociceptin/orphanin FQ-induced pain responses in conscious mice"Neuroscience. 97(1). 133-142 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yamakura,T.: "N-methyl-D-aspartate receptor channel block by meperidine is dependent on extracellular pH"Anesthesia and Analgesia. 90(4). 928-932 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tanaka,J.: "Gq protein α subunits Gαq and Gαll are localized at postsynaptic extra-junctional membrane of cerebellar Purkinje cells and hippocampal pyramidal cells"Eur.J.Neurosci.. 12(3). 781-792 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Minami,T.: "Involvement of primary afferent C-fibres in touch-evoked pain (allodynia) induced by prostaglandin E_2"Eur.J.Neurosci.. 11(6). 1849-1856 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hashimoto,K.: "Impairment of AMPA receptor function in cerebellar granule cells of ataxic mutant mouse stargazer"J.Neurosci.. 19(14). 6027-6036 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yamakura,T.: "Direct inhibition of the N-methyl-D-aspartate receptor channel by high concentrations of opioids"Anesthesiology. 91(4). 1053-1063 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Watanabe,M.: "Selective scarcity of NMDA receptor channel subunits in the stratum lucidum of the mouse hippocampal CA3"Eur.J.Neurosci.. 10(2). 478-487 (1998)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kiyama,Y.: "Increased thresholds for long-term potentiation and contextual learning in mice lacking NMDA-type receptor"J.Neurosci.. 18(17). 6704-6712 (1998)

    • Related Report
      2000 Annual Research Report
  • [Publications] Mori,H.: "Role of the carboxy-terminal region of the GluRε2 subunit in synaptic localization of NMDA receptor channel"Neuron. 21(3). 571-580 (1998)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yamakura,T.: "Sensitivity of the NMDA receptor channel to butyro-phenones is dependent on the ε2 subunit"Neuropharmacology. 37(6). 709-717 (1998)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ito,I.: "Distribution and development of NMDA receptor activities at hippocampal synapses"Neurosci.Res.. 30(2). 119-123 (1998)

    • Related Report
      2000 Annual Research Report
  • [Publications] 崎村建司: "発生工学の脳研究への応用"細胞工学. 17(10). 1605-1607 (1998)

    • Related Report
      2000 Annual Research Report
  • [Publications] 日本遺伝子治療学会 編: "遺伝子治療開発研究ハンドブック"(株)エヌ.ティー.エス. 1061 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] 久野宗 監修: "細胞工学 別冊「脳を知る」"(株)秀潤社. 205 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] 真鍋俊也 編: "無敵のバイオテクニカルシリーズ特別編「脳・神経研究の進めかた」"(株)羊土社. 188 (1998)

    • Related Report
      2000 Annual Research Report
  • [Publications] Minami, T.: "Involvement of primary afferent C-fibres in touch-evoked pain (allodynia) induced by prostaglandin E2"Eur. J. Neurosci. 11(6). 1849-1856 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hashimoto, K.: "Impairment of AMPA receptor function in cerebellar granule cells of ataxic mutant mouse stargazer"J. Neurosci.. 19(14). 6027-6036 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Watanabe, M.: "Selective scarcity of NMDA receptor channel subunits in the stratum lucidum of the mouse hippocampal CA3 subfield"Eur. J. Neurosci. 10(2). 478-487 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kiyama, Y.: "Increased thresholds for long-term potentiation & contextual learning in mice lacking the NMDA-type glutamate receptor"J. Neurosci.. 18(17). 6704-6712 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Mori, H.: "Role of the carboxy-terminal region of the GluR ε2 subunit in synaptic localization of the NMDA receptor channel"Neuron. 21(3). 571-580 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yamakura, T.: "Sensitivity of the NMDA receptor channel to butyrophenones is dependent on the ε2 subunit"Neuropharmacology. 37(6). 709-717 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ito, I.: "Distribution and development of NMDA receptor activities at hippocampal synapses examined using mice lacking the ε1 subunit gene"Neurosci. Res. 30(2). 119-123 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] 崎村建司: "発生工学の脳研究への応用"細胞工学. 17(10). 1605-1607 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] 日本遺伝子治療学会 編: "遺伝子治療開発研究ハンドブック"(株)エヌ.ティー.エス. 1061 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 久野 宗 監修: "細胞工学 別冊 「脳を知る」"(株)秀潤社. 205 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 真鍋俊也 編: "無敵のバイオテクニカルシリーズ特別編「脳・神経研究の進め方」"(株)羊土社. 188 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Watanabe, M.: "Selective scarcity of NMDA receptor channel subunits in the stratum lucidum of the mouse hippocampal CA3 subfield" Eur.J.Neurosci.10(2). 478-487 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kiyama, Y.: "Increased thresholds for long-term potentiation and contextual learning in mice lacking the NMDA-type glutamate receptor ε1 subunit" J.Neurosci.18(17). 6704-6712 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Mori, H.: "Role of the carboxy-terminal region of the GluR ε2 subunit in synaptic localization of the NMDA receptor channel" Neuron. 21(3). 571-580 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yamakura, T.: "Sensitivity of the NMDA receptor channel to butyrophenones is dependent on the ε2 subunit" Neuropharmacology. 37(6). 709-717 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 崎村健司: "発生工学の脳研究への応用" 細胞工学. 17(10). 1605-1607 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 真鍋俊也 編: "無数のバイオテクニカルシリーズ特別編「脳・神経研究の進めかた」" (株)羊土社, 188 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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