| Project/Area Number |
15200024
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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 | University of Tokyo |
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Principal Investigator |
MANABE Toshiya The University of Tokyo, Institute of Medical Science, Professor, 医科学研究所, 教授 (70251212)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥40,300,000 (Direct Cost: ¥31,000,000、Indirect Cost: ¥9,300,000)
Fiscal Year 2005: ¥13,910,000 (Direct Cost: ¥10,700,000、Indirect Cost: ¥3,210,000)
Fiscal Year 2004: ¥13,910,000 (Direct Cost: ¥10,700,000、Indirect Cost: ¥3,210,000)
Fiscal Year 2003: ¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000)
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| Keywords | glutamate / NMDA receptor / hippocampus / amygdala / learning and memory / synaptic transmission / plasticity / mouse / 恐怖学習 / 海馬 / 扁桃体 / アセチルコリン / チロシリン酸化 / アルツハイマー病 / 記憶 / 発達 |
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| Research Abstract |
The mechanism for the process of the development of learning abilities in the mammal is almost totally unknown. In this research project, we have tried to elucidate its molecular and cellular mechanism and to obtain basic results that could be used in future to improve the learning method. For this purpose, we have used hippocampal and amygdaloid slice preparations of normal and gene-targeted mutant mice to analyze synaptic transmission and plasticity electrophysiologically. In knockin mice lacking mouse apoE, but instead expressing human apoE4, LTP in the CAl region is enhanced at younger age, while LTP is unchanged in adult mice. Since basal synaptic transmission and distribution of glutamate receptors, as well as presynaptic functions, are intact in apoE4 mutant mice, age-dependent postsynaptic functional modification of LTP through lipid homeostasis is suggested. We have also examined mutant mice deficient in Ptprz, using electrophysiological, pharmacological and behavioral approaches. Mutant mice exhibit enhanced LTP in the CAl region of hippocampal slices and impaired spatial learning abilities in an age-dependent manner: young adult (less than 10 weeks old) mutant mice show normal LTP and learning abilities in Morris water maze task, whereas adult (more than 13 weeks old) mutant mice exhibit enhanced LTP and impairment in the task. The enhanced LTP is specifically canceled out by the ROCK inhibitor Y-27632. These findings suggest that the lack of Ptprz leads to aberrant activation of ROCK, and resultantly to enhanced LTP in the slice and learning impairments in the whole animal. We have also analyzed many other kinds of mutant mice lacking functional molecules, and published many research papers in scientific journals.
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