Investigation of mental disorder-related molecules through brain synapse formation mechanisms

• Project/Area Number: 24249014
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• 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)
• Co-Investigator(Renkei-kenkyūsha): YOSHIDA Tomoyuki 富山大学, 大学院医学薬学研究部, 准教授 (90372367) ; UEMURA Takeshi 信州大学, 医学部, 准教授 (00372368)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥45,110,000 (Direct Cost: ¥34,700,000、Indirect Cost: ¥10,410,000); Fiscal Year 2014: ¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000); Fiscal Year 2013: ¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000); Fiscal Year 2012: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000)
• Keywords: 神経科学 / 脳神経疾患 / 遺伝子 / シナプス / 学習 / 知的障害 / 自閉症 / 統合失調症

Outline of Final Research Achievements

We showed that glutamate receptor GluRδ2 triggers cerebellar synapse formation by clustering four neurexins through trans-synaptic interaction. In the cerebrum, IL1-receptor accessory protein-like 1 (IL1RAPL1) responsible for intellectual disability and autism spectrum disorder induces spine formation of cortical neurons through Mcf2l-RhoA-ROCK signaling. We found that in addition to IL1RAPL1, IL-1RAcP also mediates synapse formation of cortical neurons through interaction with presynaptic PTPδ. Furthermore, by analyzing the structure of crystalized PTPδ-IL1RAPL1 complex, we showed that mini-exon peptides inserted into immunoglobulin-like domains of PTPδ play critical roles in the interaction with IL1RAPL1.

Research Products

• [Journal Article] Tolerance to ethanol intoxication after chronic ethanol: role of GluN2A and PSD-95 (2015)
  • Author(s): Rachel Anne Daut, Erica Faye Busch, Jessica Ihne, Daniel Fisher, Masayoshi Mishina, Seth Grant, Marguerite Camp and Andrew Holmes
  • Journal Title: Addiction Biology Volume: 20 Pages: 259-262
  • DOI: 10.1111/adb.12110
  • Peer Reviewed
• [Journal Article] GluN2D-containing NMDA receptors mediate synaptic currents in hippocampal interneurons and pyramidal cells in juvenile mice (2015)
  • Author(s): Jakob von Engelhardt, Christina Bocklisch, Lars Toenges, Anne Herb, Masayoshi Mishina and Hannah Monyer
  • Journal Title: Frontiers in Cellular Neuroscience Volume: 9
  • DOI: 10.3389/fncel.2015.00095
  • Peer Reviewed / Open Access
• [Journal Article] Mechanisms of splicing-dependent trans-synaptic adhesion by PTPδ-IL1RAPL1/IL-1RAcP for synaptic differentiation (2015)
  • Author(s): Yamagata A., Yoshida, T., Sato, Y., Goto-Ito, S., Uemura, T., Maeda, A., Shiroshima, T., Iwasawa-Okamoto, S., Mori, H., Mishina, M., Fukai , S.
  • Journal Title: Nat Commun. Volume: 6 Pages: 6926-6926
  • DOI: 10.1038/ncomms7926
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] IL1RAPL1欠損マウスの表現型解析 (2015)
  • Author(s): 安村美里, 吉田知之, 三品昌美
  • Journal Title: 日本薬理学雑誌 Volume: 145 Pages: 187-192
  • NAID: 130005061554
• [Journal Article] Enhanced stability of hippocampal place representation caused by reduced magnesium block of NMDA receptors in the dentate gyrus (2014)
  • Author(s): Yuichiro Hayashi, Yoko Nabeshima, Katsunori Kobayashi, Tsuyoshi Miyakawa, Koichi Tanda, Keizo Takao, Hidenori Suzuki, Eisaku Esumi, Shigeru Noguchi, Yukiko Matsuda, Toshikuni Sasaoka, Tesuo Noda, Jun-ichi Miyazaki, Masayoshi Mishina, Kazuo Funabiki and Yo-ichi Nabeshima
  • Journal Title: Mol Brain. Volume: 7 Pages: 44-44
  • DOI: 10.1186/1756-6606-7-44
  • Peer Reviewed / Open Access
• [Journal Article] Lysophospholipid acyltransferases mediate phosphatidylcholine diversification to achieve the physical properties required in vivo (2014)
  • Author(s): Takeshi Harayama, Miki Eto, Hideo Shindou, Yoshihiro Kita, Eiji Otshubo, Daisuke Hishikawa, Satoshi Ishii, Kenji Sakimura, Masayoshi Mishina and Takao Shimizu
  • Journal Title: Cell metab. Volume: 20 Pages: 295-305
  • DOI: 10.1016/j.cmet.2014.05.019
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Opposing role of NMDA receptor GluN2B and GluN2D in somatosensory development and maturation (2014)
  • Author(s): Miwako Yamasaki, Rieko Okada, Chihiro Takasaki, Shima Toki, Rie Natsume, Kenji Sakimura, Masayoshi Mishina, Tetsuo Shirakawa and Masahiko Watanabe
  • Journal Title: J. Neurosci. Volume: 34 Pages: 11534-11548
  • DOI: 10.1523/jneurosci.1811-14.2014
  • NAID: 120005553664
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Loss of GluN2A-containing NMDA receptors impairs extra-dimensional set-shifting (2014)
  • Author(s): Kristin Marquardt, Monica Saha, Masayoshi Mishina, Jared W. Young and Jonathan L. Brigman
  • Journal Title: Genes, Brain and Behavior Volume: 13 Pages: 611-617
  • DOI: 10.1111/gbb.12156
  • Peer Reviewed
• [Journal Article] IL1RAPL1 knockout mice show learning deficiency, memory decline, hyperactivity and reduced anxiety-like behaviours. (2014)
  • Author(s): Misato Yasumura, Tomoyuki Yoshida, Maya Yamazaki, Manabu Abe, Rie Natsume, Kouta Kanno, Takeshi Uemura, Keizo Takao, Kenji Sakimura, Takefumi Kikusui, Tsuyoshi Miyakawa, Masayoshi Mishina
  • Journal Title: Sci Rep. Volume: 4: 6613 Pages: 6613-6613
  • DOI: 10.1038/srep06613
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Striatal dopamine D1 receptor is essential for contextual fear conditioning (2014)
  • Author(s): Masaru Ikegami, Takeshi Uemura, Ayumi Kishioka, Kenji Sakimura and Masayoshi Mishina
  • Journal Title: Sci Rep. Volume: 4 Pages: 3976-3976
  • DOI: 10.1038/srep03976
  • NAID: 120007100114
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Consolidation of auditory fear memories formed by weak unconditioned stimuli requires NMDA receptor activation and de novo protein synthesis in the striatum. (2013)
  • Author(s): Ayumi Kishioka, Takeshi Uemura, Fumiaki Fukushima and Masayoshi Mishina
  • Journal Title: Molecular Brain Volume: 6
  • DOI: 10.1186/1756-6606-6-17
  • NAID: 120007100115
  • Peer Reviewed
• [Journal Article] Dock3 interaction with a glutamate-receptor NR2D subunit protects neurons from excitotoxicity (2013)
  • Author(s): Ning Bai, Hideki Hayashi, Tomomi Aida, Kazuhiko Namekata, Takayuki Harada, Masayoshi Mishina and Kohichi Tanaka
  • Journal Title: Molecular Brain Volume: 6 Pages: 22-22
  • DOI: 10.1186/1756-6606-6-22
  • Peer Reviewed
• [Journal Article] IL1RAPL1 associated with mental retardation and autism regulates the formation and stabilization of glutamatergic synapses of cortical neurons through RhoA signaling pathway (2013)
  • Author(s): Takashi Hayashi, Tomoyuki Yoshida, Moonjin Ra, Ryo Taguchi and Masayoshi Mishina
  • Journal Title: PLoS One Volume: 8
  • DOI: 10.1371/journal.pone.0066254
  • Peer Reviewed
• [Journal Article] Role of convergent activation of glutamatergic and dopaminergic systems in the nucleus accumbens in the development of methamphetamine psychosis and dependence (2013)
  • Author(s): Masayuki Miyazaki, Yukihiro Noda, Akihiro Mouri, Kazuto Kobayashi, Masayoshi Mishina, Toshitaka Nabeshima and Kiyofumi Yamada
  • Journal Title: International Journal of Neuropsychopharmacology Volume: 16 Pages: 1341-1350
  • DOI: 10.1017/s1461145712001356
  • Peer Reviewed
• [Journal Article] NMDA receptor subunits have different roles in NMDA-induced neurotoxicity in the retina (2013)
  • Author(s): Ning Bai, Tomomi Aida, Michiko Yanagisawa, Sayaka Katou, Kenji Sakimura, Masayoshi Mishina and Kohichi Tanaka
  • Journal Title: Molecular Brain Volume: 6
  • DOI: 10.1186/1756-6606-6-34
  • Peer Reviewed
• [Journal Article] Synapse formation in the brain (2013)
  • Author(s): Masayoshi Mishina, Tomoyuki Yoshida, Misato Yasumura and Takeshi Uemura
  • Journal Title: Cortical Development: Neural Diversity and Neocortical Organization Volume: 1 Pages: 229-247
  • DOI: 10.1007/978-4-431-54496-8_11
• [Journal Article] Phenotypic characterization of orofacial movement topography in mutants with disruption of amino acid mechanisms: glutamate N2A/B/D [GluRε1/2/4] subtypes and the GABA synthesizing enzyme GAD65 (2013)
  • Author(s): Katsunori Tomiyama, Risako Kato, Yaeko Hara, Masayuki Kobayashi, Masayoshi Mishina, Yuchio Yanagawa, Anthony Kinsella, Noriaki Koshikawa and John L. Waddington
  • Journal Title: Neuroscience Volume: 250 Pages: 743-754
  • DOI: 10.1016/j.neuroscience.2013.07.038
  • Peer Reviewed
• [Journal Article] Involvement of the N-methyl-D-aspartate receptor GluN2D subunit in phencyclidine-induced motor impairment, gene expression, and increased Fos immunoreactivity (2013)
  • Author(s): Hideko Yamamoto, Etsuko Kamegaya, Wakako Sawada, Ryota Hasegawa, Toshifumi Yamamoto, Yoko Hagino, Yukio Takamatsu, Kazuhide Imai, Hisashi Koga, Masayoshi Mishina and Kazutaka Ikeda
  • Journal Title: Mol Brain Volume: 6 Pages: 56-56
  • DOI: 10.1186/1756-6606-6-56
  • Peer Reviewed
• [Journal Article] robing the modulation of acute ethanol intoxication by pharmacological manipulation of the NMDAR glycine coagonist site (2013)
  • Author(s): Lauren Debrouse, Benita Hurd, Carly Kiselycznyk, Aaron Plitt, Alyssa Todaro, Masayoshi Mishina, Seth Grant, Marguerite Camp, Ozge Gunduz Cinar and Andrew Holmes
  • Journal Title: Alcoholism: Clinical and Experimental Research Volume: 37 Pages: 223-233
  • DOI: 10.1111/j.1530-0277.2012.01922.x
  • Peer Reviewed
• [Journal Article] Age-dependent dystonia in striatal Gγ7 deficient mice is reversed by the dopamine D2 receptor agonist pramipexole (2013)
  • Author(s): Keita Sasaki, Tatsuro Yamasaki, Idowu O Omotuyi, Masayoshi Mishina and Hiroshi Ueda
  • Journal Title: Journal of Neurochemistry Volume: 124 Pages: 844-854
  • DOI: 10.1111/jnc.12149
  • Peer Reviewed
• [Journal Article] Interleukin-1 receptor accessory protein organizes neuronal synaptogenesis as a cell adhesion molecule (2012)
  • Author(s): T.Yoshida
  • Journal Title: Journal of Neuroscience Volume: 32 Pages: 2588-2600
  • DOI: 10.1523/jneurosci.4637-11.2012
  • Peer Reviewed
• [Journal Article] GluRδ2 assembles four neurexins into trans-synaptic triad to trigger synapse formation (2012)
  • Author(s): Lee, S., Uemura, T., Yoshida, T., Mishina, M.
  • Journal Title: Journal of Neuroscience Volume: 32 Pages: 4688-46701
  • DOI: 10.1523/jneurosci.5584-11.2012
  • Peer Reviewed
• [Journal Article] Molecular mechanism of parallel fiber-Purkinje cell synapse formation (2012)
  • Author(s): Masayoshi Mishina, Takeshi Uemura, Misato Yasumura and Tomoyuki Yoshida
  • Journal Title: Frontiers in Neural Circuits Volume: 6 Pages: 90-90
  • DOI: 10.3389/fncir.2012.00090
  • Peer Reviewed
• [Presentation] Re-assessment of mitochondrial biogenesis-related signaling pathways in neurons (2014)
  • Author(s): Takumi Yokokawa, Naoko Morimura, Masayoshi Mishina, Hidekazu Tanaka, Takashi Fujita, Nobumasa Iwanaka, Tatsuya Hayashi, Takeshi Hashimoto
  • Organizer: The 37th Annual Meeting of the Molecular Biology Society of Japan
  • Place of Presentation: パシフィコ横浜（神奈川県）
  • Year and Date: 2014-11-27
• [Presentation] Striatal dopamine D1 receptor is essential for contextual fear conditioning (2014)
  • Author(s): Masayoshi Mishina, Masaru Ikegami, Takeshi Uemura, Ayumi Kishioka and Kenji Sakimura
  • Organizer: The 37th Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: パシフィコ横浜（神奈川県）
  • Year and Date: 2014-09-13
• [Presentation] Manipulating critical period by controlling synaptic GluN2B: live imaging of corticospinal axons (2014)
  • Author(s): Isoo Noriko, Ohno Takae, Isowaki Mutsumi, Murabe Naoyuki, Masayoshi Mishina and Sakurai Masaki
  • Organizer: The 37th Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: パシフィコ横浜（神奈川県）
  • Year and Date: 2014-09-13
• [Presentation] Developmental change in GluN2B and critical period for corticospinal synapse (2014)
  • Author(s): Isowaki Mutsumi, Ohno Takae, Isoo Noriko, Fukuda Satoshi, Masayoshi Mishina and Sakurai Masaki
  • Organizer: The 37th Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: パシフィコ横浜（神奈川県）
  • Year and Date: 2014-09-13
• [Presentation] Synapse formation in the brain and developmental disorders
  • Author(s): Masayoshi Mishina
  • Organizer: The 12th Meeting of Asia Pacific Federation of Pharmacologists
  • Place of Presentation: Shanghai, China
  • Invited
• [Presentation] Negative emotional states in the GluN2D subunit knockout mice
  • Author(s): Hideko Yamamoto, Etsuko Kamegaya, Yoko Hagino, Yukio Takamatsu, Toshifumi Yamamoto, Masayoshi Mishina, Kazutaka Ikeda
  • Organizer: The 43rd Annual Meeting of the Society for Neuroscience
  • Place of Presentation: San Diego, California, USA
• [Presentation] IL1RAPL1 regulates the formation and stabilization of glutamatergic synapses of cortical neurons through RhoA signaling pathway
  • Author(s): Takashi Hayashi, Tomoyuki Yoshida, Masayoshi Mishina
  • Organizer: The 36th Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: 京都府、国立京都国際会館
• [Presentation] Behavioral phenotypes of IL1RAPL1 knockout mice
  • Author(s): Misato Yasumura, Tomoyuki Yoshida, Keizo Takao, Maya Yamazaki, Manabu Abe, Takeshi Uemura, Tsuyoshi Miyakawa, Kenji Sakimura and Masayoshi Mishina
  • Organizer: The 36th Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: 京都府、国立京都国際会館
• [Presentation] Phenotypic analysis of IL1RAPL1 knockout mice
  • Author(s): Misato Yasumura and Masayoshi Mishina
  • Organizer: The 87th Annual Meeting of The Japanese Pharmacological Society
  • Place of Presentation: 宮城県、仙台国際センター
• [Presentation] Is it possible to manipulate the critical period?
  • Author(s): Takae Ohno, Mutsumi Takewaki, Noriko Isono, Naoyuki Murabe, Hitoshi Maeda, Satoshi Fukuda, Masayoshi Mishina and Masaki Sakurai
  • Organizer: The 35th Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: 愛知県、名古屋国際会議場
• [Presentation] Interleukin-1 receptor accessory protein functions as a neuronal cell adhesion molecule to organize synaptogenesis.
  • Author(s): Tomoyuki Yoshida, Tomoko Shiroshima, Sung-Jin Lee, Misato Yasumura, Takeshi Uemura, Xigui Chen, Yoichiro Iwakura and Masayoshi Mishina
  • Organizer: The 35th Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: 愛知県、名古屋国際会議場
• [Presentation] GluRδ2 regulates synapse formation by clustering four neurexins through triad formation.
  • Author(s): Takeshi Uemura, Sung-Jin Lee, Tomoyuki Yoshida and Masayoshi Mishina
  • Organizer: The 35th Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: 愛知県、名古屋国際会議場
• [Presentation] Closure of the critical period in developmental corticospinal plasticity could be regulated by the synaptic expression levels of GluN2B-subunit containing NMDA receptors.
  • Author(s): Noriko Isono, Takae Ohno, Mutsumi Isowaki, Naoyuki Murabe, Masayoshi Mishina and Masaki Sakurai
  • Organizer: The 35th Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: 愛知県、名古屋国際会議場
• [Presentation] IL1RAPL1 associated with mental retardation and autism regulates the formation and stabilization of glutamatergic synapses of cortical neurons through RhoA signaling pathway
  • Author(s): Takashi Hayashi, Tomoyuki Yoshida, Masayoshi Mishina
  • Organizer: The 86 th Annual Meeting of The Japanese Pharmacological Society
  • Place of Presentation: 福岡県、福岡国際会議場
• [Book] 分子脳科学 (2015)
  • Author(s): 三品昌美、高橋良輔、虫明元、小林和人、橋本浩一、河崎弘志、山口正洋、伊藤誠二、松崎政紀、喜田聡、饗場篤、岩坪威、齊藤尚亮、上田泰己、山中章弘、尾崎紀夫、功刀浩、内匠透、池田和隆、大隅典子、影山龍一郎、吉田知之、杉山清佳他
  • Total Pages: 312
  • Publisher: 化学同人