| Project/Area Number |
16200024
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neuroscience in general
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| Research Institution | KEIO UNIVERSITY |
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Principal Investigator |
YUZAKI Michisuke Keio University, School of Medicine, Professor, 医学部, 教授 (40365226)
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| Co-Investigator(Kenkyū-buntansha) |
IIJIMA Takatoshi Keio University, School of Medicine, Assistant Professor, 医学部, 助手 (90383702)
松田 信爾 慶應義塾大学, 医学部, 助手 (60321816)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥49,790,000 (Direct Cost: ¥38,300,000、Indirect Cost: ¥11,490,000)
Fiscal Year 2006: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000)
Fiscal Year 2005: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2004: ¥21,970,000 (Direct Cost: ¥16,900,000、Indirect Cost: ¥5,070,000)
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| Keywords | glutamate receptor / synapse formation / cerebellum / Purkinje cell / synaptic plasticity / transgenic mouse |
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| Research Abstract |
The ionotropic glutamate receptors play important roles in not only neurotransmission, but also synaptic plasticity and neurotoxicity in the mammalian brain. They are subdivided into four subfamilies: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, kainate receptors, N-methyl-D-aspartate receptors, and delta glutamate receptors. The delta2 glutamate receptor (GluRd2), which is predominantly expressed in Purkinje cells, plays a crucial role in cerebellar functions : mutant mice with a disrupted GluRd2 gene (delta2-null mice) display impaired synapse formation and abrogated long-term depression (LTD), a form of synaptic underlying motor learning. Despite its importance, the mechanisms by which delta2 regulates cerebellar functions have remained elusive. Several fundamental questions, such as whether GluRd2 is activated by glutamate and whether GluRd2 forms ion channels, have remained elusive largely because there were no specific pharmacologic tools to manipula
… More
te the function of GluRd2.
To circumvent the problem caused by the lack of pharmacologic tools, we employed a "transgenic rescue" approach by exploiting the fact that the several important regions, such as the putative ligand-binding and the channel pore domains, of GluRd2 shares considerable similarity with those of AMPA receptors. We introduced a mutant GluRd2 transgene, in which the conserved residues in the putative ligand-binding or channel pore domains were disrupted, into GluRd2-null Purkinje cells by either virus vectors or transgenic mice. Surprisingly, the mutant GluRd2 transgenes were as effective as the wild-type GluRd2 in rescuing the GluRd2-null mice. Thus, we propose that GluRd2 may not be activated by glutamate and may not function as an ion channel although it belongs to the "ionotropic glutamate receptor" family. In contrast, abrogated LTD was not restored in GluRd2-null Purkinje cells by the transduction of a mutant GluRd2 transgene lacking the C-terminal domain. Therefore, GluRd2 may function by modulating an intracellular signalling pathway through its C-terminal intracellular domain, to which several adaptor proteins bind. Less
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