REGULATORY MOLECULES OF CENTRAL SYNAPSES

• Project/Area Number: 21249012
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: The University of Tokyo
• Principal Investigator: MISHINA Masayoshi 東京大学, 大学院・医学系研究科, 教授 (80144351)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥47,320,000 (Direct Cost: ¥36,400,000、Indirect Cost: ¥10,920,000); Fiscal Year 2011: ¥15,860,000 (Direct Cost: ¥12,200,000、Indirect Cost: ¥3,660,000); Fiscal Year 2010: ¥14,950,000 (Direct Cost: ¥11,500,000、Indirect Cost: ¥3,450,000); Fiscal Year 2009: ¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000)
• Keywords: グルタミン酸受容体 / 中枢シナプス / シナプス形成 / 精神疾患 / 大脳 / ニューレキシン / Cbln / GluRδ1 / PTPσ / 神経細胞 / プロテオミクス / 小脳プルキニエ細胞 / シナプス分子 / グルタミン酸受容体δ2 / Cbln1 / クロスリンカー / ゼブラフィッシュ / シナプス小胞 / カルシウムシグナル

Research Abstract

Elucidation of molecular mechanisms that regulate synapse formation is prerequisite for the understanding of neural wiring, higher brain functions and mental disorders. Here, we show that glutamate receptor GluRδ2 mediates cerebellar synapse formation by interacting with presynaptic neurexins through Cbln1. These results suggest that the combination of systematic proteomics and functional synapse formation assays provide efficient screening of molecules responsible for synapse formation and function, contributing to the development of brain neuropharmacology.

Research Products

• [Journal Article] Glutamate receptor δ1 induces preferentially inhibitory presynaptic differentiation of cortical neurons by interacting with neurexins through cerebellin pecursor protein (Cbln)subtypes (2012)
  • Author(s): Yasumura, M., Yoshida, T., Lee, S., Uemura, T., Joo, J., Mishina, M.
  • Journal Title: J.Neurochem. Volume: (E-pub on 24 Jan 2012) Issue: 5 Pages: 705-716
  • DOI: 10.1111/j.1471-4159.2011.07631.x
  • Peer Reviewed
• [Journal Article] Interleukin-1 receptor accessory protein organizes neuronal synaptogenesis as a cell adhesion molecule (2012)
  • Author(s): T.Yoshida
  • Journal Title: J Neurosci Volume: 32 Issue: 8 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: J.Neurosci. Volume: 32 Issue: 13 Pages: 4688-4701
  • DOI: 10.1523/jneurosci.5584-11.2012
  • Peer Reviewed
• [Journal Article] Protein tyrosine phosphataseσregulates the synapse number of zebrafish olfactory sensory neurons (2011)
  • Author(s): Chen, X., Yoshida, T., Sagara, H., Mikami, Y. and Mishina, M
  • Journal Title: J. Neurochem Volume: 119 Issue: 3 Pages: 532-543
  • DOI: 10.1111/j.1471-4159.2011.07411.x
  • Peer Reviewed
• [Journal Article] IL-1 receptor accessory protein-like 1 associated with mental retardation and autism mediates synapse formation by trans-synaptic interaction with protein tyrosine phosphatase δ (2011)
  • Author(s): T.Yoshida
  • Journal Title: J Neurosci Volume: 31 Issue: 38 Pages: 13485-13499
  • DOI: 10.1523/jneurosci.2136-11.2011
  • Peer Reviewed
• [Journal Article] NMDA receptor signaling in oligodendrocyte progenitors is not required for oligodendrogenesis and myelination (2011)
  • Author(s): Biase, L. D., Kang, S., Potter, E., Fukaya, F., Pucak, M., Mishina, M., Calabresi, P. and Bergles, D
  • Journal Title: J. Neurosci Volume: 31 Issue: 35 Pages: 12650-12662
  • DOI: 10.1523/jneurosci.2455-11.2011
  • Peer Reviewed
• [Journal Article] Remodeling of monoplanar Purkinje cell dendrites during cerebellar circuit formation (2011)
  • Author(s): Kaneko, M., Yamaguchi, K., Eiraku, M., Sato, M., Takata, N., Kiyohara, Y., Mishina, M., Hirase, H., Hashikawa, T. and Kengaku, M
  • Journal Title: PLoS ONE Volume: 6 Issue: 5 Pages: e20108-e20108
  • DOI: 10.1371/journal.pone.0020108
  • Peer Reviewed
• [Journal Article] Differential interactions of cerebellin precursor protein (Cbln) subtypes and neurexin variants for synapse formation of cortical neurons (2011)
  • Author(s): Joo, J.Y.; Lee, S.J.; Uemura, T., et al
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 406(6) Issue: 4 Pages: 627-632
  • DOI: 10.1016/j.bbrc.2011.02.108
  • Peer Reviewed
• [Journal Article] Glutamate Receptor delta 2 Is Essential for Input Pathway-Dependent Regulation of Synaptic AMPAR Contents in Cerebellar Purkinje Cells (2011)
  • Author(s): Yamasaki, M.; Miyazaki, T.; Azechi, H., et al
  • Journal Title: Journal of Neuroscience Volume: 31(9) Issue: 9 Pages: 3362-3374
  • DOI: 10.1523/jneurosci.5601-10.2011
  • Peer Reviewed
• [Journal Article] NR3A-containing NMDARs promote neurotransmitter release and spike timing-dependent plasticity (2011)
  • Author(s): Larsen, R.S.; Corlew, R.J.; Henson, M.A., et al
  • Journal Title: Nature Neuroscience Volume: 14(3) Issue: 3 Pages: 338-344
  • DOI: 10.1038/nn.2750
  • Peer Reviewed
• [Journal Article] Identification and characterization of a novel zebrafish semaphorin. (2011)
  • Author(s): Taniguchi, M.Masuda, T., Mikami, Y., Kimura, M., Yoshida, T., Mishina, M., Shimizu, T.
  • Journal Title: Neurosci.Lett. Volume: 488 Pages: 215-220
  • Peer Reviewed
• [Journal Article] NR3A-containing NMDA receptors promote neurotransmitter release and spike timing-dependent plasticity. (2011)
  • Author(s): Larsen, R.S., Corlew, R.J.Henson, M.A., Roberts, A.C., Mishina, M., Watanabe, M., Lipton, S.A., Nakanishi, N., Perez-Otano, I., Weinberg, R.J., Philpot, B.D.
  • Journal Title: Nature Neurosci. Volume: 14 Pages: 338-344
  • Peer Reviewed
• [Journal Article] Glutamate receptor δ2 is essential for input pathway-dependent regulation of synaptic AMPAR contents in cerebellar Purkinje cells. (2011)
  • Author(s): Yamasaki, M., Miyazaki, T., Azechi, H., Abe, M., Natsume, R., Hagiwara, T., Aiba, A., Mishina, M., Sakimura, K., Watanabe, M.
  • Journal Title: J.Neurosci. Volume: 31 Pages: 3362-3374
  • Peer Reviewed
• [Journal Article] Differential interactions of cerebellin precursor protein (Cbln)subtypes and neurexin variants for synapse formation of cortical neurons. (2011)
  • Author(s): Joo, J., Lee, S., Uemura, T.Yoshida, T., Yasumura, M.Watanabe, M., Mishina, M.
  • Journal Title: Biochem.Biophys.Res.Commun. Volume: 406 Pages: 627-632
  • Peer Reviewed
• [Journal Article] Remodeling of monoplanar Purkinje cell dendrites during cerebellar circuit formation. (2011)
  • Author(s): Kaneko, M., Yamaguchi, K., Eiraku, M., Sato, M., Takata, N., Kiyohara, Y., Mishina, M., Hirase, H., Hashikawa, T., Kengaku, M.
  • Journal Title: PLoS ONE Volume: 印刷中(掲載確定)
  • Peer Reviewed
• [Journal Article] The physiological roles of vesicular GABA transporter during embryonic development : a study using knockout mice (2010)
  • Author(s): Hayashi, R., Nakazato, Y., Takamori, S., Ebihara, S., Uematsu, M., Mishina, M., Miyazaki, J., Yokoyama, M., Konishi, S., Inoue, K., Fukuda, A., Fukumoto, M., Nakamura, K., Obata, K., and Yanagawa, Y
  • Journal Title: Mol. Brain Volume: 3. 40 Issue: 1
  • DOI: 10.1186/1756-6606-3-40
  • Peer Reviewed
• [Journal Article] Ablation of glutamate receptor GluRδ2 in adult Purkinje cells causes multiple innervation of climbing fibers by inducing aberrant invasion to parallel fiber innervation territory (2010)
  • Author(s): Miyazaki, T., Yamasaki, M., Takeuchi, T., Sakimura, K., Mishina, M. and Watanabe, M
  • Journal Title: J. Neurosci Volume: 30 Issue: 45 Pages: 15196-15209
  • DOI: 10.1523/jneurosci.0934-10.2010
  • Peer Reviewed
• [Journal Article] Essential role of NMDA receptor channelε4 subunit(GluN2D) in the effects of phencyclidine, but not methamphetamine (2010)
  • Author(s): Hagino, Y., Kasai, S., Han, W., Yamamoto, H., Nabeshima, T., Mishina, M. and Ikeda, K
  • Journal Title: PLoS ONE Volume: 5 Issue: 10 Pages: e13722-e13722
  • DOI: 10.1371/journal.pone.0013722
  • Peer Reviewed
• [Journal Article] Specific involvement of postsynaptic GluN2B-containing NMDA receptors in the developmental elimination of corticospinal synapses (2010)
  • Author(s): Ohno, T., Maeda, H., Murabe, N., Kamiyama, T., Yoshioka, N., Mishina, M. and Sakurai, M
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 107 Issue: 34 Pages: 15252
  • DOI: 10.1073/pnas.0906551107
  • Peer Reviewed
• [Journal Article] Trans-synaptic interaction of GluRδ2 and neurexin through Cbln1 mediates synapse formation in the cerebellum (2010)
  • Author(s): Uemura, T., Lee, S., Yasumura, M., Takeuchi, T., Yoshida, T., Ra, M., Taguchi, R., Sakimura, K. and Mishina, M.
  • Journal Title: Cell Volume: 141 Issue: 6 Pages: 1068-1079
  • DOI: 10.1016/j.cell.2010.04.035
  • Peer Reviewed
• [Journal Article] Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability (2010)
  • Author(s): Mozhui, K., Karlsson, R-M., Kash, T. L., Ihne, J., Norcross, M., Patel, S., Farrell, M. R., Hill, E., Martin, K., Camp, M., Fitzgerald, P. J., Ciobanu, D. C., Sprengel, R., Mishina, M., Wellman, C. L., Winder, D. G., Williams, R. W., and Holmes, A
  • Journal Title: J. Neurosci Volume: 30 Issue: 15 Pages: 5357-5367
  • DOI: 10.1523/jneurosci.5017-09.2010
  • Peer Reviewed
• [Journal Article] Estrogen regulates the expression of N-methyl-D-aspartate(NMDA) receptor subunit epsilon 4(Grin2d), that is essential for the normal sexual behavior in female mice (2010)
  • Author(s): Ikeda, K., Fukushima, T., Ogura, H., Tsukui, T., Mishina, M., Muramatsu, M. and Inoue, S
  • Journal Title: FEBS Lett Volume: 584 Issue: 4 Pages: 806-810
  • DOI: 10.1016/j.febslet.2009.12.054
  • Peer Reviewed
• [Journal Article] Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability. (2010)
  • Author(s): Mozhui, K., Karlsson, R-M., Kash, T.L., Ihne, J., Norcross, M., Patel, S., Farrell, M.R., Hill, E., Martin, K., Camp, M., Fitzgerald, P.J., Ciobanu, D.C., Sprengel, R., Mishina, M., Wellman, C.L., Winder, D.G., Williams, R.W., Holmes, A.
  • Journal Title: J.Neurosci. Volume: 30 Pages: 5357-5367
  • Peer Reviewed
• [Journal Article] Trans-synaptic interaction of GluR62 and neurexin through Cbinl mediates synapse formation in the cerebellum. (2010)
  • Author(s): Uemura, T., Lee, S., Yasumura, M., Takeuchi, T., Yoshida, T., Ra, M., Taguchi, R., Sakimura, K., Mishina, M.
  • Journal Title: Cell Volume: 141 Pages: 1068-1079
  • Peer Reviewed
• [Journal Article] Specific involvement of postsynaptic G1uRN2B-containing NMDA receptors in the developmental elimination of corticospinal synapses. (2010)
  • Author(s): Ohno, T., Maeda, H., Murabe, N., Kamiyama, T., Yoshioka, N., Mishina, M., Sakurai, M.
  • Journal Title: Proc.Natl.Acad.Sci.USA Volume: 107 Pages: 15252-15257
  • Peer Reviewed
• [Journal Article] Essential role of NMDA receptor channel e4 subunit (G1uN2D)in the effects of phencyclidine, but not methamphetamine. (2010)
  • Author(s): Hagino, Y., Kasai, S., Han, W., Yamamoto, H., Nabeshima, T., Mishina, M., Ikeda, K.
  • Journal Title: PLoS ONE Volume: 5(電子出版) Pages: 13722-13722
  • Peer Reviewed
• [Journal Article] Ablation of glutamate receptor GluRδ2 in adult Purkinje cells causes multiple innervation of climbing fibers by inducing aberrant invasion to parallel fiber innervation territory. (2010)
  • Author(s): Miyazaki, T., Yamasaki, M., Takeuchi, T., Sakimura, K.Mishina, M., Watanabe, M.
  • Journal Title: J.Neurosci. Volume: 30 Pages: 15196-15209
  • Peer Reviewed
• [Journal Article] The physiological roles of vesicular GABA transporter during embryonic development : a study using knockout mice. (2010)
  • Author(s): Hayashi, R., Nakazato, Y., Takamori, S., Ebihara, S., Uematsu, M., Mishina, M., Miyazaki, J., Yokoyama, M., Konishi, S., Inoue, K., Fukuda, A., Fukumoto, M., Nakamura, K., Obata, K., Yanagawa, Y.
  • Journal Title: Mol.Brain Volume: 3(電子出版) Pages: 40-40
  • Peer Reviewed
• [Journal Article] Estrogen regulates the expression of N-methyl-D-aspartate (NMDA) receptor subunit epsilon 4 (Grin2d), that is essential for the normal sexual behavior in female mice. (2010)
  • Author(s): Ikeda, K., Fukushima, T., Ogura, H., Tsukui, T., Mishina, M., Muramatsu, M., Inoue, S.
  • Journal Title: FEBS Lett. Volume: 584 Pages: 806-810
  • Peer Reviewed
• [Journal Article] Regulation of synaptic vesicle accumulation and axon terminal remodeling during synapse formation by distinct Ca^<2+> signaling (2009)
  • Author(s): Yoshida, T., Uchida, S. and Mishina, M
  • Journal Title: J. Neurochem Volume: 111 Issue: 1 Pages: 160-170
  • DOI: 10.1111/j.1471-4159.2009.06309.x
  • Peer Reviewed
• [Journal Article] NR2A at CA1 synapses is obligatory for the susceptibility of hippocampal plasticity to sleep loss (2009)
  • Author(s): Longordo, F., Kopp, C., Mishina, M., Lujan, R. and Luthi, A
  • Journal Title: J. Neurosci Volume: 29 Issue: 28 Pages: 9026-9041
  • DOI: 10.1523/jneurosci.1215-09.2009
  • Peer Reviewed
• [Journal Article] NR2A at CA1 synapses is obligatory for the susceptibility of hippocampal plasticity to sleep loss. (2009)
  • Author(s): Longordo, F., Kopp, C., Mishina, M., Lujan, R., Luthi, A.
  • Journal Title: J.Neurosci. Volume: 29 Pages: 9026-9041
  • Peer Reviewed
• [Journal Article] Influence of parallel fiber-Purkinje cell synapse formation on postnatal development of climbing fiber-Purkinje cell synapses in the cerebellum. (2009)
  • Author(s): Hashimoto, K., Yoshida, T., Sakimura, K., Mishina, M., Watanabe, M., Kano, M.
  • Journal Title: Neuroscience Volume: 162 Pages: 601-611
  • Peer Reviewed
• [Journal Article] Regulation of synaptic vesicle accumulation and axon terminal remodeling during synapse formation by distinct Ca^<2+> signaling. (2009)
  • Author(s): Yoshida, T., Uchida, S., Mishina, M.
  • Journal Title: J.Neurochem. Volume: 111 Pages: 160-170
  • Peer Reviewed
• [Presentation] Synapse formation in the brain (2011)
  • Author(s): Masayoshi Mishina
  • Organizer: The 4^<th> Molecular and Cellular Cognition Society-Asia Symposium
  • Place of Presentation: Seoul, Korea(招待講演)
  • Year and Date: 2011-09-19
• [Presentation] Molecular insights into synapse formation from GluRδ2-neurexin and IL1RAPL1-RPTP systems (2011)
  • Author(s): Masayoshi Mishina
  • Organizer: ISN-ESN-2011 Statellite Meeting : The Synapse from Physiology to Pathology
  • Place of Presentation: Stresa, Italy(招待講演)
  • Year and Date: 2011-09-07
• [Presentation] Identification of a novel ligand for glutamate receptor δ2. (2010)
  • Author(s): Mishina, M., Uemura, T., Lee, S., Yasumura, M., Yoshida, T.
  • Organizer: The 16th World Congress of Basic and Clinical Pharmacology
  • Place of Presentation: Copenhagen, Denmark
  • Year and Date: 2010-07-22
• [Presentation] Control of synaptic connection by Cbln1 in the adult cerebellum. (2010)
  • Author(s): M.Yasumura, T.Takeuchi, T.Uemura, K.Sakimura, M.Mishina
  • Organizer: The 83^<nd> Annual Meeting of the Japanese Pharmacological Society
  • Place of Presentation: 大阪国際会議場、大阪府
  • Year and Date: 2010-03-17
• [Presentation] Identification of Cbln1 as a novel ligand for glutamate receptor δ2. (2010)
  • Author(s): T.Uemura, S-J.Lee, M.Yasumura, T.Yoshida, M.Ra, R.Taguchi, M.Mishina
  • Organizer: The 83^<nd> Annual Meeting of the Japanese Pharmacological Society
  • Place of Presentation: 大阪国際会議場、大阪府
  • Year and Date: 2010-03-17
• [Presentation] High-affinity and selective binding of Cbln1 to glutamate receptor δ2. (2010)
  • Author(s): S.J.Lee, T.Uemura, M.Mishina
  • Organizer: The 83^<nd> Annual Meeting of the Japanese Pharmacological Society
  • Place of Presentation: 大阪国際会議場、大阪府
  • Year and Date: 2010-03-17
• [Presentation] Identification of a novel ligand for glutamate receptorδ2(July 22) (2010)
  • Author(s): Mishina, M., Uemura, T., Lee, S., Yasumura, M. and Yoshida, T
  • Organizer: The 16^<th> World Congress on Basic and Clinical Pharmacology
  • Place of Presentation: Copenhagen, Denmark
• [Presentation] Glutamate receptor signaling in learning and neural wiring (2010)
  • Author(s): Mishina, M
  • Organizer: Korean Society for Biochemistry and Molecular Biology(KSBMB) Annual Meeting
  • Place of Presentation: Seoul, Korea
• [Presentation] The role of the N-terminal domain of glutamate receptor δ2 in synapse formation. (2009)
  • Author(s): T.Uemura, M.Mishina
  • Organizer: The 32^<nd> Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: 名古屋国際会議場、愛知県
  • Year and Date: 2009-09-17
• [Remarks] 新聞報道(1)科学新聞「小脳のグルタミン酸受容体シナプス形成導く精神疾患解明期待東大・三品教授ら成果」2010年6月11日
• [Remarks] (2)朝日新聞「脳機能障害克服へ一歩」2010年6月4日
• [Remarks] (3)日本経済新聞「つなぎ目構造解明東大、自閉症薬などに道」2010年5月28日
• [Remarks] (4)日刊工業新聞「東大、分子機構を解明シナプス結合の形成」2010年5月28日