2002 Fiscal Year Final Research Report Summary
Investigation on the regulation of synaptic transmission by glial molecules
| Project/Area Number |
10214206
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas (B)
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | National Center of Neurology and Psychiatry |
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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)
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| 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)
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| Project Period (FY) |
1998 – 2001
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| Keywords | glia / gene / glutamate / ubiquitin / receptor / transporter / retina / synapse |
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| 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.
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[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
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[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)
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「研究成果報告書概要(欧文)」より
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[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
