Study on a new synaptic accumulation mechanism of AMPA receptor by lipid-related molecules

• Project/Area Number: 15K08151
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General anatomy (including histology/embryology)
• Research Institution: University of Fukui
• Principal Investigator: XIE MINJUE 福井大学, 子どものこころの発達研究センター, 助教 (40444210)
• 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) ; 黒田 一樹 福井大学, 学術研究院医学系部門, 助教 (60557966)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: Phldb2 / LTD / LTP / CamKII / PIP3 / AMPAR / CamkII / AMPA-R

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 it completely. Here, we determined that Phldb2, of which pleckstrin-homology domain is highly sensitive to PIP3, functions as a phosphoinositide-signaling mediator for synaptic plasticity. Phldb2 bound to postsynaptic scaffolding molecule PSD-95 and was crucial for localization and turnover of PSD-95 in the spine. Phldb2 also bound to GluA1, GluA2 and CaMKII. Phldb2 was indispensable for the interaction between NMDA receptors and CaMKII, and the synaptic density of AMPA receptors. Therefore, PIP3-responsive Phldb2 is pivotal for induction and maintenance of LTP. Phldb2 unexpectedly bound to AP2 and this was necessary for AMPA receptor endocytosis. Long-term memory formation as well as LTP and LTD was indeed impaired in our Phldb2-/- mice.

Research Products

• [Journal Article] Effects of Buyang Huanwu decoction combined with edaravone on mitochondrial apoptotic pathway of nerve cells in mice with cerebral ischemia-reperfusion injury (2017)
  • Author(s): Zhong FF, Wu CL, Zhang YX, Sun XF, Xie MJ, Sato M.
  • Journal Title: Int J Clin Exp Med Volume: 10(4) Pages: 6749-6755
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Subcellular distribution of non-muscle myosin IIb is controlled by FILIP through Hsc70. (2017)
  • Author(s): Yagi H, Takabayashi T, Xie MJ, Kuroda K, Sato M
  • Journal Title: PLOS ONE Volume: 12 Issue: 2 Pages: e0172257-e0172257
  • DOI: 10.1371/journal.pone.0172257
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Filamin A interacting protein plays a role in proper positioning of callosal projection neurons in the cortex (2016)
  • Author(s): Yagi H, Oka Y, Komada M, Xie MJ, Noguchi K, Sato M.
  • Journal Title: Neurosci Lett Volume: 612 Pages: 18-24
  • DOI: 10.1016/j.neulet.2015.11.049
  • Peer Reviewed / Open Access
• [Journal Article] DBZ regulates cortical cell positioning and neurite development by sustaining the anterograde transport of Lis1 and DISC1 through control of Ndel1 dual-phosphorylation. (2015)
  • Author(s): 1.Okamoto, M., Iguchi, T., Hattori, T., Matsuzaki, S., Koyama, Y., Taniguchi, M., Kodama, M., Xie, M-J., Yagi, H., Shimizu, S., Konishi, Y., Yoshimi, T., Tachibana, T., Fujieda, S., Katayama, T., Ito, A., Hirotsune, S., Tohyaman, M. and Sato, M.
  • Journal Title: J Neurosci Volume: 18 Issue: 7 Pages: 2942-2958
  • DOI: 10.1523/jneurosci.5029-13.2015
  • Peer Reviewed / Open Access
• [Presentation] Phosphoinositide responsive Phldb2 regulates synaptic plasticity through glutamate receptors (2017)
  • Author(s): Xie MJ, Ishikawa Y, Yagi H, Matsuzaki H, Fukazawa Y, Sato M.
  • Organizer: The Society for Neuroscience 47th annual meeting
  • Int'l Joint Research
• [Presentation] Phosphoinositide responsive Phldb2 regulates synaptic plasticity (2016)
  • Author(s): Xie MJ, Yagi H, Iguchi T, Oka Y, Fukazawa Y, Matsuzaki H, Iwata K, Ishikawa Y, Sato, M.
  • Organizer: The Society for Neuroscience 46th annual meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-11-13
  • Int'l Joint Research
• [Presentation] Phldb2, a phosphoinositide mediator, regulates synaptic plasticity through AMPA reseptor and CaMKⅡ (2016)
  • Author(s): 謝 敏かく、八木秀司、猪口徳一、岡 雄一郎、黒田一樹、深沢有吾、松崎秀夫、岩田圭子、石川保幸、佐藤 真
  • Organizer: 第38回日本生物学的生物精神医学会・第59回日本神経化学会合同年会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2016-09-08
• [Presentation] 膜脂質結合タンパク質Phldb2を介したAMPA受容体局在制御機構 (2016)
  • Author(s): 謝 敏カク、八木 秀司、 猪口 徳一、 岡 雄一郎、 黒田 一樹、 深澤有吾、松崎秀夫、岩田圭子、 柚崎 通介、松田 信爾、石川 保幸、佐藤 真
  • Organizer: 第121回日本解剖学会総会・全国学術集会
  • Place of Presentation: ビックパレットふくしま
  • Year and Date: 2016-03-30
  • Invited
• [Presentation] FILIP-related molecule binds to NMDA receptor and controls spine maturation and synaptic function of the hippocampal neuron (2015)
  • Author(s): Kazuki Kuroda, Hideshi Yagi, Min-Jue Xie, Yugo Fukazawa, Yuichiro Oka, Tokuichi Iguchi, Makoto Sato
  • Organizer: Society for Neuroscience 2015
  • Place of Presentation: Chicago
  • Year and Date: 2015-10-19
  • Int'l Joint Research
• [Presentation] Phldb2はシナプスの可塑性を制御する (2015)
  • Author(s): 謝 敏カク、八木 秀司、 猪口 徳一、 岡 雄一郎、 黒田 一樹、 深澤有吾、松崎秀夫、岩田圭子、 柚崎 通介、松田 信爾、石川 保幸、佐藤 真
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸国際会議場、神戸国際展示場
  • Year and Date: 2015-07-30
  • Int'l Joint Research