2006 Fiscal Year Final Research Report Summary
Maintenance of synapses and formation of memory in the adult brain : new mechanisms regulated by the delta2 glutamate receptor
| 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)
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| Project Period (FY) |
2004 – 2006
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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
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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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[Journal Article] Ca^<2+> permeability of the channel pore is not essential for the δ2 glutamate receptor to regulate synaptic plasticity and motor coordination.2007
Author(s)
Kakegawa, W., Miyazaki, T., Hirai, H., Motohashi, J., Mishina, M., Watanabe, M., Yuzaki, M.
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Journal Title
Journal of Physiology (London) 579・3
Pages: 729-735
Description
「研究成果報告書概要(和文)」より
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[Journal Article] The extreme C-terminus of GluRdelta2 is essential for induction of long-term depression in cerebellar slices.2007
Author(s)
Kohda, K., Kakegawa, W., Matsuda, S., Nakagami, R., Kakiya, N., Yuzaki, M.
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Journal Title
European Journal of Neuroscience 25・5
Pages: 1357-1362
Description
「研究成果報告書概要(和文)」より
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