| Project/Area Number |
18K06823
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 48010:Anatomy-related
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| Research Institution | University of Fukui |
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Principal Investigator |
Xie Min Jue 福井大学, 子どものこころの発達研究センター, 助教 (40444210)
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| Co-Investigator(Kenkyū-buntansha) |
佐藤 真 大阪大学, 連合小児発達学研究科, 教授 (10222019)
深澤 有吾 福井大学, 学術研究院医学系部門, 教授 (60343745)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | Phldb2 / BDNF / drebrin A / drebrin / F-actin / PSD-95 / GluR2-R / PIP3 / 構造的可塑性 |
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| Outline of Final Research Achievements |
The essential involvement of phosphoinositides in synaptic plasticity is well-established, but incomplete knowledge of the downstream molecular entities prevents us from understanding their signalling cascades completely. Here, we determined that Phldb2, of which pleckstrin-homology domain is highly sensitive to PIP3, functions as a phosphoinositide-signalling mediator for synaptic plasticity. BDNF application caused Phldb2 recruitment toward postsynaptic membrane in dendritic spines, whereas PI3K inhibition resulted in its reduced accumulation. Phldb2 bound to postsynaptic scafolding molecule PSD-95 and drebrin A, and were crucial for localization of PSD-95 and drebrin A in the spine. Phldb2 was indispensable the synaptic density of AMPA receptors and spine formation. Therefore, PIP3-responsive Phldb2 is pivotal for induction and maintenance of LTP. Memory formation was impaired in our Phldb2－/－ mice.
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| Academic Significance and Societal Importance of the Research Achievements |
シナプス伝達効率を動的に制御（シナプス可塑性）する仕組みは、学習記憶のモデルとして盛んに研究され、関連遺伝子やタンパク質の同定とその役割の理解が深まりつつある。本研究では、膜脂質の一種ホスファチジルイノシトール(3,4,5)三リン酸(PIP3)と特異的に結合するPhldb2は、シナプスが形成されるスパインにPIP3依存的に局在し、シナプス可塑性、構造および学習記憶に重要な役割があることを見出した。この研究から得られる知見は記憶・学習機能を支える基本原理の理解に十分に貢献できることが期待でき、更に、神経・精神疾患の原因やその治療法の研究にも役立つ可能性がある。
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