Exploring the mechanism of the entry of endoplasmic reticulum into dendritic spines for modifying excitatory synaptic transmission

• Project/Area Number: 17K07108
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Nagoya University
• Principal Investigator: Ageta-Ishihara Natsumi 名古屋大学, 理学研究科, 講師 (60547561)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: 細胞骨格 / 学習 / 記憶

Outline of Final Research Achievements

Discrimination among different spatial contexts depends on the hippocampal dentate gyrus (DG). However, molecular basis remains unclear. Here we find that Septin-null (Sept-KO) mice retain memory of spatial context for 2h, but not for 24h, in spatial pattern separation test. To narrow down brain regions responsible for the cognitive impairment, we conduct local subacute depletion of SEPT from the bilateral DG of wild-type mice, and local supplementation of SEPT into the bilateral DG of KO mice, which respectively recapitulates and rescues the defect. The perforant path-DG synapses in KO mice are normal, except for a significant scarcity of smooth endoplasmic reticulum (sER), a Ca2+ reservoir in dendritic spines. The sER anomaly is recapitulated by SEPT depletion from primary cultured rat DG granule cells (DGCs). The DGC-selective requirement of SEPT will illuminate a novel gating or translocation mechanism that regulates the entry of sER from dendritic shaft into spines.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、学術的には細胞小器官の移動が記憶保持に影響を及ぼすことを示す初めての概念となる。社会的には、認知症患者と診断される数年前の時点でも空間pattern separation機能が低下することが報告されていることから、空間弁別課題の長期記憶保持の基盤となる分子メカニズムの解明は薬剤探索や記憶保持機能低下を抑制する食品の開発に繋がることが期待できる。

Research Products

• [Journal Article] CDC42EP4, a perisynaptic scaffold protein in Bergmann glia, is required for glutamatergic tripartite synapse configuration. (2018)
  • Author(s): Ageta-Ishihara N, Konno K, Yamazaki M, Abe M, Sakimura K, Watanabe M, Kinoshita M.
  • Journal Title: Neurochem Int Volume: S0197-0186 Issue: 17 Pages: 30442-4
  • DOI: 10.1016/j.neuint.2018.01.003
  • Peer Reviewed / Open Access
• [Journal Article] UBL3 modification influences protein sorting to small extracellular vesicles. (2018)
  • Author(s): Ageta H, Ageta-Ishihara N, Hitachi K, Karayel O, Onouchi T, Yamaguchi H, Kahyo T, Hatanaka K, Ikegami K, Yoshioka Y, Nakamura K, Kosaka N, Nakatani M, Uezumi A, Ide T, Tsutsumi Y, Sugimura H, Kinoshita M, Ochiya T, Mann M, Setou M, Tsuchida K.
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 3936-3936
  • DOI: 10.1038/s41467-018-06197-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Activity- and septin-dependent extension of smooth ER into dendritic spines as a synaptic basis of memory consolidation (2020)
  • Author(s): 小坂優介、上田(石原)奈津実、深澤有吾、見学美根子、高雄敬三、宮川剛、 尾藤晴彦、木下専
  • Organizer: 2019年度文部科学省新学術領域研究 学術研究支援基盤形成 先端モデル動物支援プラットフォーム成果発表会
• [Presentation] A synaptic basis of spatial pattern separation in the hippocampal dentate gyrus is activity- and septin-dependent extension of smooth endoplasmic reticulum into dendritic spines (2020)
  • Author(s): Ageta-Ishihara Natsumi, Asami Yurika, Fukumasu Naoto, Sakakibara Kodai, Fuse Naoki, Mitsui Riku, Fukazawa Yugo, Kengaku Mineko, Takao Keizo, Miyakawa Tsuyoshi, Inokuchi Kaoru, Bito Haruhiko, Kinoshita Makoto
  • Organizer: 第16回成体脳のニューロン新生懇談会
• [Presentation] A novel UBL3 modification influences protein sorting to small extracellular vesicles (2019)
  • Author(s): Ageta Hiroshi, Ageta-Ishihara Natsumi, Hitachi K, Onouchi T, Yamaguchi H, Yoshioka Y, Kosaka N, Ide T, Kinoshita M, Ochiya T, Setou M, Tsuchida K.
  • Organizer: ISEV2019, Symposium session: EV Biogenesis II
  • Int'l Joint Research / Invited
• [Presentation] 神経活動とセプチンに依存した樹状突起棘への小胞体侵入による記憶の長期化 (2019)
  • Author(s): 木下専, 上田(石原)奈津実, 深澤有吾, 宮川剛, 高雄啓三, 尾藤晴彦
  • Organizer: 第42回日本神経科学大会 第62回日本神経化学大会
• [Presentation] 空間弁別の個性を形成する環境的要因と遺伝的要因の複合解析 (2019)
  • Author(s): 上田(石原)奈津実、木下専
  • Organizer: 「個性」創発脳第四回領域会議
• [Presentation] 個性の階層的理解を目指した評価系の確立 -空間弁別の分子・細胞学的基盤 - (2019)
  • Author(s): 上田(石原)奈津実、榊原広大、福枡直人、藤原里沙子、小坂優介、高雄啓三、宮川剛、尾藤晴彦、井ノ口馨、深澤有吾、木下専
  • Organizer: 「個性」創発脳第四回領域会議
• [Presentation] 環境要因により影響を受ける認知機能に対するアプローチ (2019)
  • Author(s): 上田(石原)奈津実、木下専
  • Organizer: 資生堂女性研究者サイエンスグラント受賞者 特別講演会
  • Invited
• [Presentation] 長期記憶保持に必要な分子・細胞基盤の解明 (2019)
  • Author(s): 上田(石原)奈津実、木下専
  • Organizer: 2019 GTR Seeds Seminar
  • Invited
• [Presentation] An activity-regulated septin subunit SEPT3 is required for the entry of sER into dendritic spines and spatial discrimination. (2018)
  • Author(s): Ageta-Ishihara N, Fukazawa Y, Takao K, Miyakawa T, Bito H, Inokuchi K,
  • Organizer: Gordon Research Conference “Cell Biology of the Neuron”
  • Int'l Joint Research
• [Presentation] Spatial discrimination defects caused by chronic, systemic loss of a septin subunit is recapitulated by its acute, local depletion in the hippocampal dentate gyrus (2018)
  • Author(s): Ageta-Ishihara N, Takao K, Miyakawa T, Hioki H, Bito H, Inokuchi K, Kinoshita M.
  • Organizer: 第1回国際シンポジウム “Towards Understanding INDIVIDUALITY”
  • Int'l Joint Research
• [Presentation] Requirement of a septin subunit SEPT3 in the dentate gyrus granule cells for dendritic spine maturation and spatial discrimination (2018)
  • Author(s): Sakakibara K, Fukumasu N, Ageta-Ishihara N, Fukazawa Y, Takao K, Miyakawa T, Bito H, Kinoshita M.
  • Organizer: The 6th Neural Circuits Joint Workshop
• [Presentation] Unexpected motor and histopathological phenotype found in mice that lack SEPT7 in the cerebellum (2018)
  • Author(s): Ageta-Ishihara N, Kurita H, Yamazaki M, Abe M, Fukazawa Y, Sakimura K, Kinoshita M.
  • Organizer: The 6th Neural Circuits Joint Workshop
• [Presentation] A septin-dependent synaptic regulation required for spatial discrimination (2018)
  • Author(s): 上田(石原)奈津実, 木下 専
  • Organizer: 第95回日本生理学会大会
  • Invited
• [Presentation] 空間弁別に必要なセプチン依存的シナプス制御 (2017)
  • Author(s): 上田(石原)奈津実, 深澤有吾, 鈴木悠大, 増田啓吾, 高雄啓三, 宮川剛, 尾藤晴彦, 木下 専
  • Organizer: 第40回神経科学学会