Specificity and molecular mechanism of synapse formation

• Project/Area Number: 16H04676
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Ritsumeikan University
• Principal Investigator: MISHINA Masayoshi 立命館大学, 総合科学技術研究機構, 教授 (80144351)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2018: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: 神経科学 / シナプス形成 / 脳神経疾患 / 脳・神経 / 遺伝子 / 蛋白質 / タンパク質 / シナプスオーガナイザー / 脳の発達 / 脳高次機能 / 精神疾患 / 神経回路 / 細胞接着分子

Outline of Final Research Achievements

We found a non-canonical pathway of pre- and postsynaptic interactions by unbiased screening of synaptic molecules interacting synapse organizers, PTPδ and neurexins, using synapse inducing system in primary neuronal cultures and protein cross-linking method. The physiological significance of this new interaction between synapse organizers was revealed by analyzing mutant mice with mutations specifically disrupting the non-canonical pathway. We also found that neurexins are essential for the survival of cerebellar granule neurons by analyzing triple knockout mice lacking neurexin 1, 2 and 3.

Academic Significance and Societal Importance of the Research Achievements

シナプス形成誘導時にシナプスオーガナイザーと相互作用する分子を特異的かつ網羅的に単離するunbiased screeningにより、脳シナプス形成の分子機構の解明を推進した。シナプスオーガナイザーの変異は知的障害、自閉症、統合失調症などに密接に関連することが知られており、シナプス形成の分子機構解明は、シナプス形成の破綻が原因になることが知られている精神疾患のバイオマーカーや治療薬の開発に貢献することが期待される。

Research Products

• [Journal Article] Acute administration of ketamine attenuates the impairment of social behaviors induced by social defeat stress exposure as juveniles via activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (2019)
  • Author(s): Hasegawa Sho、Yoshimi Akira、Mouri Akihiro、Uchida Yoji、Hida Hirotake、Mishina Masayoshi、Yamada Kiyofumi、Ozaki Norio、Nabeshima Toshitaka、Noda Yukihiro
  • Journal Title: Neuropharmacology Volume: 148 Pages: 107-116
  • DOI: 10.1016/j.neuropharm.2018.12.020
  • Peer Reviewed
• [Journal Article] Cognitive impairment that is induced by (R)-ketamine is abolished in NMDA GluN2D receptor subunit knockout mice. (2019)
  • Author(s): Ide S, Ikekubo Y, Mishina M, Hashimoto K, Ikeda K
  • Journal Title: Int J Neuropsychopharmacol Volume: 22 Issue: 7 Pages: 449-452
  • DOI: 10.1093/ijnp/pyz025
  • Peer Reviewed / Open Access
• [Journal Article] MTSS1 Regulation of Actin-Nucleating Formin DAAM1 in Dendritic Filopodia Determines Final Dendritic Configuration of Purkinje Cells (2018)
  • Author(s): Kawabata Galbraith Kelly、Fujishima Kazuto、Mizuno Hiroaki、Lee Sung-Jin、Uemura Takeshi、Sakimura Kenji、Mishina Masayoshi、Watanabe Naoki、Kengaku Mineko
  • Journal Title: Cell Reports Volume: 24 Issue: 1 Pages: 95-106
  • DOI: 10.1016/j.celrep.2018.06.013
  • NAID: 120006489939
  • Peer Reviewed / Open Access
• [Journal Article] NMDA receptor GluN2A subunit deletion protects against dependence-like ethanol drinking (2018)
  • Author(s): Nicholas J. Jury, Anna K. Radke, Dipanwita Pati, Adrina Kocharian, Masayoshi Mishina, Thomas L. Kash and Andrew Holmes
  • Journal Title: Behavioural Brain Research Volume: 353 Pages: 124-128
  • DOI: 10.1016/j.bbr.2018.06.029
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Altered synaptic and extrasynaptic NMDA receptor properties in substantia nigra dopaminergic neurons from mice lacking the GluN2D subunit (2018)
  • Author(s): Paul G. Morris, Masayoshi Mishina and Susan Jones
  • Journal Title: Frontiers in Cellular Neuroscience Volume: 12 Pages: 354-354
  • DOI: 10.3389/fncel.2018.00354
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Deficiency of AMPAR?Palmitoylation Aggravates Seizure Susceptibility (2018)
  • Author(s): Itoh Masayuki、Yamashita Mariko、Kaneko Masaki、Okuno Hiroyuki、Abe Manabu、Yamazaki Maya、Natsume Rie、Yamada Daisuke、Kaizuka Toshie、Suwa Reiko、Sakimura Kenji、Sekiguchi Masayuki、Wada Keiji、Hoshino Mikio、Mishina Masayoshi、Hayashi Takashi
  • Journal Title: The Journal of Neuroscience Volume: 38 Issue: 47 Pages: 10220-10235
  • DOI: 10.1523/jneurosci.1590-18.2018
  • Peer Reviewed / Open Access
• [Journal Article] Perturbed expression pattern of the immediate early gene Arc in the dentate gyrus of GluA1 C‐terminal palmitoylation‐deficient mice (2018)
  • Author(s): Itoh Masayuki、Okuno Hiroyuki、Yamada Daisuke、Yamashita Mariko、Abe Manabu、Natsume Rie、Kaizuka Toshie、Sakimura Kenji、Hoshino Mikio、Mishina Masayoshi、Wada Keiji、Sekiguchi Masayuki、Hayashi Takashi
  • Journal Title: Neuropsychopharmacology Reports Volume: 39 Issue: 1 Pages: 61-66
  • DOI: 10.1002/npr2.12044
  • Peer Reviewed / Open Access
• [Journal Article] Role of NMDA receptor GluN2D subunit in the antidepressant effects of enantiomers of ketamine. (2017)
  • Author(s): Ide S, Ikekubo Y, Mishina M, Hashimoto K, Ikeda K
  • Journal Title: J Pharmacol Sci Volume: 135(3) Issue: 3 Pages: 138-140
  • DOI: 10.1016/j.jphs.2017.11.001
  • Peer Reviewed / Open Access
• [Journal Article] Loss of GluN2D subunit results in social recognition deficit, social stress, 5-HT2C receptor dysfunction, and anhedonia in mice. (2017)
  • Author(s): Yamamoto H, Kamegaya E, Hagino Y, Takamatsu Y, Sawada W, Matsuzawa M, Ide S, Yamamoto T, Mishina M, Ikeda K
  • Journal Title: Neuropharmacology Volume: 112(Pt A) Pages: 188-197
  • DOI: 10.1016/j.neuropharm.2016.07.036
  • Peer Reviewed / Open Access
• [Journal Article] Modulation of long interspersed nuclear element-1 in the mouse hippocampus during maturation (2016)
  • Author(s): Mikako Ueno, Tadashi Okamura, Masayoshi Mishina and Yukihito Ishizaka
  • Journal Title: Mobile Genetic Elements Volume: 6 Issue: 4 Pages: e1211980-e1211980
  • DOI: 10.1080/2159256x.2016.1211980
  • Peer Reviewed / Open Access
• [Journal Article] The decline in synaptic GluN2B and rise in inhibitory neurotransmission determine the end of a critical period (2016)
  • Author(s): Noriko Isoo, Takae Ohno, Mutsumi Isowaki, Satoshi Fukuda, Naoyuki Murabe, Hiroaki Mizukami, Keiya Ozawa, Masayoshi Mishina, and Masaki Sakurai
  • Journal Title: Scientific Reports Volume: 6 Issue: 1
  • DOI: 10.1038/srep34196
  • Peer Reviewed / Open Access
• [Presentation] The long-lasting antidepressant effects and the cognitive impairment effects of (R)-ketamine are abolished in NMDA receptor GluN2D subunit knockout mice (2018)
  • Author(s): Soichiro Ide, Yuiko Ikekubo, Masayoshi Mishina, Kenji Hashimoto and Kazutaka Ikeda
  • Organizer: The 31st International College of Neuropsychopharmacology World Congress
  • Int'l Joint Research
• [Presentation] Role of NMDA receptor GluN2D subunit in the antidepressant effects and the cognitive impairment effects of enantiomers of ketamine (2018)
  • Author(s): Soichiro Ide, Yuiko Ikekubo, Masayoshi Mishina, Kenji Hashimoto and Kazutaka Ikeda
  • Organizer: The 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] パルミトイル化によるAMPA受容体制御の異常は発作感受性を上昇させる (2018)
  • Author(s): 伊藤政之、金子雅規、阿部学、山崎真弥、夏目里恵、山田大輔、崎村建司、関口正幸、和田圭司、三品昌美、林崇
  • Organizer: 第139回日本薬理学会関東部会
• [Presentation] AMPA受容体パルミトイル化サイトの欠損は発作感受性を上昇させる (2018)
  • Author(s): 伊藤政之、山下真梨子、金子雅規、奥野浩行、阿部学、山崎真弥、夏目里恵、山田大輔、貝塚利恵、諏訪麗子、崎村建司、関口正幸、和田圭司、星野幹雄、三品昌美、林崇
  • Organizer: 第41回日本分子生物学会
• [Presentation] Palmitoylation-dependent regulation of the AMPA receptor modulates seizure susceptibility (2017)
  • Author(s): Masayuki Itoh, Mariko Yamashita, Hiroyuki Okuno, Manabu Abe, Maya Yamazaki, Rie Natsume, Toshie Kaizuka, Kenji Sakimura, Mikio Hoshino, Masayoshi Mishina and Takashi Hayashi
  • Organizer: The 90th Annual Meeting of The Japanese Pharmacological Society
  • Place of Presentation: 長崎ブリックホール（長崎県・長崎市）
  • Year and Date: 2017-03-16
• [Presentation] 小脳顆粒細胞特異的ニューレキシントリプルノックアウトマウスの作成と解析 (2017)
  • Author(s): 植村健, 鈴木絵美, 小池梨絵, 川瀬詩織, 栗原大河, 﨑村建司, 三品昌美, 田渕克彦
  • Organizer: 第40回日本神経科学大会
• [Presentation] マイクロエキソンの選択的スプライシングによってつくりだされるPtprdバリアントの発現解析 (2017)
  • Author(s): 田端-今井彩子, 畦地健司, 森寿, 三品昌美, 吉田知之
  • Organizer: 第40回日本神経科学大会
• [Presentation] パルミトイル化サイト欠失型AMPA受容体ノックインマウスにおける興奮性神経活動の亢進と発作感受性の上昇 (2017)
  • Author(s): 伊藤政之, 山下真梨子, 山田大輔, 奥野浩行, 阿部学, 山崎真弥, 夏目里恵, 金子雅規, 貝塚利恵, 崎村建司, 関口正幸, 和田圭司, 星野幹雄, 三品昌美, 林崇
  • Organizer: 第40回日本神経科学大会
• [Presentation] ケタミンの抗うつ作用と認知機能障害におけるNMDA受容体GluN2Dサブユニットの役割 (2017)
  • Author(s): 井手聡一郎, 池窪結子, 橋本謙二, 三品昌美, 池田和隆
  • Organizer: 第47回日本神経精神薬理学会
• [Presentation] 大脳異常興奮の抑制に関わるAMPA受容体パルミトイル化依存的なシナプス機能制御 (2017)
  • Author(s): 金子雅規, 伊藤政之, 山下真梨子, 奥野浩行, 阿部学, 山崎真弥, 夏目里恵, 貝塚利恵, 崎村建司, 星野幹雄, 三品昌美, 林崇
  • Organizer: 第47回日本神経精神薬理学会
• [Presentation] From Molecular Regulators of Synapses to Learning and Memory (2016)
  • Author(s): Masayoshi Mishina
  • Organizer: The 14th National Conference of Chinese Pharmacology Society
  • Place of Presentation: Beijing (China)
  • Year and Date: 2016-10-24
  • Invited
• [Presentation] Maintenance of excitatory-inhibitory balance in brain by AMPA receptor palmitoylation (2016)
  • Author(s): Mariko Yamashita, Hiroyuki Okuno, Manabu Abe, Maya Yamazaki, Rie Natsume, Kenji Sakimura, Mikio Hoshino, Masayoshi Mishina and Takashi Hayashi
  • Organizer: The 39th Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-07-21
• [Presentation] Effects of antiepileptic agents on GluR palmitoylation-dependent regulation of excitatory-inhibitory balance in brain (2016)
  • Author(s): Takashi Hayashi, Mariko Yamashita, Hiroyuki Okuno, Manabu Abe, Maya Yamazaki, Rie Natsume, Kenji Sakimura, Mikio Hoshino and Masayoshi Mishina
  • Organizer: The 46th Annual Meeting of the Japanese Society of Neuropsychopharamacology
  • Place of Presentation: Seoul (Korea)
  • Year and Date: 2016-07-03