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Investigation on the regulation of synaptic transmission by glial molecules

Research Project

Project/Area Number 10214206
Research Category

Grant-in-Aid for Scientific Research on Priority Areas (B)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionNational Center of Neurology and Psychiatry

Principal Investigator

WADA Keiji  Department of Degenerative Neurological Diseases, Director, 神経研究所・疾病研究第四部, 部長 (70250222)

Co-Investigator(Kenkyū-buntansha) NODA Mami  Kyushu University, Graduate School of Pharmaceutical Sciences Associate Professor, 大学院・薬学研究院, 助教授 (80127985)
SEKIGUCHI Masayuki  Department of Degenerative Neurological Diseases, Section Chief, 神経研究所・疾病研究第四部, 室長 (80260339)
Project Period (FY) 1998 – 2001
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥29,100,000 (Direct Cost: ¥29,100,000)
Fiscal Year 2001: ¥7,200,000 (Direct Cost: ¥7,200,000)
Fiscal Year 2000: ¥7,200,000 (Direct Cost: ¥7,200,000)
Fiscal Year 1999: ¥7,200,000 (Direct Cost: ¥7,200,000)
Fiscal Year 1998: ¥7,500,000 (Direct Cost: ¥7,500,000)
Keywordsglia / gene / glutamate / ubiquitin / receptor / transporter / retina / synapse / 光変性 / ラット / 神経栄養因子 / ミクログリア / FGF / 神経細胞死 / trkC / p75 / 軸索 / 変性 / 脱ユビキチン化酵素 / ポジショナルクローニング / 脱感作 / けいれん / プラスミノーゲン / ATP
Research Abstract

In this study, we aimed to elucidate the molecular mechanism of glia-neuron interaction, and to develop essential therapy for brain diseases based on the glial regulation of neural transmission. We achieved investigations on the following subjects ;
1) Identification of an animal model for investigating glial contribution on neurodegeneration
The gracile axonal dystrophy mouse is pathologically characterized by presynaptic degeneration at axon terminals. The mouse is suitable for investigating the functional change of glial cells during loss of presynaptic structures We employed a positional cloning approach to identify the gene for the mutation. We found that a segment of ubiquitin C-terminal hydrolase L1 gene is deleted in the mutant.
2) Development of a new therapy of retinal degeneration by modification of glial cell function
We demonstrate a novel pathway of light-induced photoreceptor apoptosis involving the low-affinity neurotrophin receptor p75 (p75NTR). Retinal degeneration upregulated both p75NTR and the high-affinity neurotrophin receptor TrkC in different parts of Muller glial cells. Exogenous neurotrophin-3 (NT-3) increased, but nerve growth factor (NGF) decreased basic fibroblast growth factor (bFGF) production in Muller cells, which can directly rescue photoreceptor apoptosis. Blockade of p75NTR prevented bFGF reduction and resulted in both structural and functional photoreceptor survival in vivo.
3) Miscellaneous
We found that PEPA is a novel allosteric modulator of AMPA type glutamate receptors. PEPA affects desensitization but not deactivation of the receptors. We generated mice lacking the function of glial glutamate transporter, GLAST.
These findings are useful for further investigation of glial contribution on neural transmission.

Report

(5 results)
  • 2002 Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (20 results)

All Other

All Publications (20 results)

  • [Publications] Kurihara, L. et al.: "Loss of Uch-L1 and Uch-L3 leads to neurodegeneration, posterior paralysis and dysphagia"Hum. Mol. Genet.. 10. 1963-1970 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Harada, T. et al.: "Modification of glial-neuronal interactions prevents photoreceptor apoptosis during light-induced retinal degeneration"Neuron. 26. 533-541 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Saigoh, K. et al.: "Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in gad mice"Nat. Genet.. 23. 47-51 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Harada, T. et al.: "Functions of the two glutamate transporters GLAST and GLT-1 in the retina"Proc. Natl. Acad. Sci. USA. 95. 4663-4666 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kurihara, L.J., Kikuchi, T., Wada, K., and Tilghman, S.M.: "Loss of Uch-L1 and Uch-L3 leads to neurodegeneration, posterior paralysis and dysphagia"Hum. Mol. Genet.. 10. 1963-1970 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Harada, T., Harada, C., Nakayama, N., Okuyama, S., Yoshida, K., Kohsaka, S., Matsuda, H., and Wada, K.: "(2000) Modification of glial-neuronal interactions prevents photoreceptor apoptosis during light-induced retinal degeneration"Neuron. 26. 533-541 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Saigoh, K., Wang, Y.-L., Suh, J.G., Yamanishi, T., Sakai, Y., Kiyosawa, H., Harada, T., Ichihara, N., Wakana, S., Kikuchi, T. and Wada, K.: "(2001) Intragenic deletion in the geneencoding ubiquitin carboxy-terminal hydrolase in gad mouse"Nature Genet.. 23. 47-51 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Harada, T., Harada, C., Watanabe, M., Inoue, Y., Sakagawa, T., Nakayama, N., Sasaki, S., Okuyama, S., Watase, K., Wada, K. and Tanaka, K.: "(2001) Functions of the two glutamate transporters GLAST and GLT-1 in the retina"Proc. Nat1. Acad. Sci. USA. 95. 4663-4666 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sekiguch, M.et al.: "The AMPA receptor allosteric potentiator PEPA ameliorates post-"NeuroReport. 12. 2947-2950 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Osawa, Y.et al.: "Cloning,expression,and mapping of a mouse gene,Uchl4,highly homologous--"Biochem.Biophys.Res.Comm.. 283. 627-633 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kurihara, L.J.et al.: "Loss of Uch-L1 and Uch-L3 leads to neurodegeneration,posterior--"Human Mol.Genet.. 10. 1963-1970 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Harada,T., et al.: "Modification of glial-neuronal cell interactions prevents photoreceptor-"Neuron. 533-541 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Saigoh, K.et al.: "Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in…"Nature Genetics. 23. 47-51 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kojima, S.et al.: "Optical detection of synapticall induced glutamate transport in hippocampal slices"Journal of Neuroscience. 19. 2580-2588 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nakagawa, T.et al.: "Potentiating effects of 4-[2-(phenylsulfonylamino) ehtylthio]-2, 6-difluoro…"Neuroscience Research. 35. 217-223 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Watase,K.et al.: "Motor discoordination and increased susceptibility to cerebellar injury in GLAST---" Eur.J.Nerurosci.10. 976-988 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sekiguchi,M.et al.: "Pharmacological detection of AMPA receptor heterogeneity by use of two allosteric---" Br.J.Pharmacol.123. 1294-1303 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Harada,T.et al.: "Light-induced retinal degeneration suppresses developmental progression of flip---" J.Neurosci.18. 3336-3343 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Harada,T.et al.: "Functions of the two glutamate transporters GLAST and GLT-1 in the retina." Proc.Natl.Acad.Sci.USA. 95. 4663-4666 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Inage,Y.W.et al.: "Expression of two glutamate transporters GLAST and EAAT4 in the human---" J.Neuropathol.Exp.Neurol.57. 554-562 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2018-03-28  

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