2001 Fiscal Year Final Research Report Summary
Studies on the nitric oxide cascade involved in neuronal plasticity.
| Project/Area Number |
12680790
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 | RIKEN |
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Principal Investigator |
ENDO Shogo Neuronal Circuit Mechanism Research Group, RIKEN Senior Scientist, 神経回路メカニズム研究グループ, 上級研究員 (60192514)
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| Co-Investigator(Kenkyū-buntansha) |
IKEDA Toshio Behavioral Genetics laboratory, Staff RIKEN Scientist, 行動遺伝学技術開発チーム, 研究員 (80252526)
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| Project Period (FY) |
2000 – 2001
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| Keywords | LTD / Cerebellum / Nitric oxide / cGMP / Synaptic transmission |
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| Research Abstract |
One of the most attractive but fundamental question in the field of neuroscience is to understand the mechanisms underlying learning and memory. There is a consensus that the memory is formed by the flexibility of synapses called neuronal plasticity. However, the molecular mechanisms responsible for neuronal plasticity remain unclear. We used cerebellar long-term depression (LTD), that is an activity-dependent depression of synaptic transmission from parallel fiber onto Purkinje cells, as a model for the neuronal plasticity and studied the molecular mechanisms underlying LTD. It is reported that a variety of molecules are involved in the induction of LTD. We focused on the signal transduction cascade initiated with nitric oxide (NO) which plays an essential role in the induction of LTD. As a downstream component of NO-cGMP-PKG (cGMP-dependent protem kinase) cascade we molecularly identified G-substrate that is a good substrate for PKG and localized in cerebellar Purkinje cells. We have cloned human, rat and mouse cDNAs and characterized. The mouse G-substrate gene was also identified and characterized. The mRNA of G-substrate was exclusively expressed in cerebellar Purkinje cells. G-substrate protein was observed not only in their cell bodies but also in dendrites. Furthermore, G-substrate was revealed to be a specific and strong inhibitor of protein phosphatase-1 and -2A upon the phosphorylation by PKG. We have generated the mice deficient in G-substrate gene. The mice were fertile and appearance was normal, but showed the loss of LTD in cerebellar slice preparation. The results suggest an essential role of G-substrate in the induction of LTD via its function as a protein phosphatase inhibitor. Further studies on the cerebellum- or LTD-dependent behavior of G-substrate knock-out mice will reveal the physiological function of G-substrate in learning and memory.
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