Molecular mechanisms for calcium-mediated refinement of competitive synaptic wiring in the brain

2011 Fiscal Year Final Research Report

• Project/Area Number: 19100005
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Neuroscience in general
• Research Institution: Hokkaido University
• Principal Investigator: WATANABE Masahiko 北海道大学, 大学院・医学研究科, 教授 (70210945)
• Co-Investigator(Kenkyū-buntansha): SAKIMURA Kenji 新潟大学, 脳研究所, 教授 (40162325) ; KANO Masanobu 東京大学, 大学院医学系研究科, 教授 (40185963) ; AIBA Atsu 東京大学, 大学院医学系研究科, 教授 (20271116) ; FUKAYA Masahiro 北里大学, 医学部, 講師 (10360900) ; YAMASAKI Miwako 北海道大学, 大学院医学研究科, 講師 (10431305) ; MIYAZAKI Taisuke 北海道大学, 大学院医学研究科, 助教 (90374230)
• Co-Investigator(Renkei-kenkyūsha): KANO Masanobu 東京大学, 大学院・医学系研究科, 教授 (40185963) ; AIBA Atsu 東京大学, 大学院・医学系研究科, 教授 (20271116) ; FUKAYA Masahiro 北里大学, 医学部, 講師 (10360900) ; YAMASAKI Miwako 北海道大学, 大学院・医学研究科, 講師 (10431305) ; MIYAZAKI Taisuke 北海道大学, 大学院・医学研究科, 助教 (90374230)
• Project Period (FY): 2007 – 2011
• Keywords: シナプス回路 / シナプス刈込み / グルタミン酸受容体 / カルシウムイオン

Research Abstract

Synaptic circuits in neonates are characterized by excess, overlapping and entangled wiring. These immature circuits are refined into functional and mature ones through use-dependent and activity-dependent strengthening and weakening/elimination of immature synapses. Through this process, almost all of higher brain functions develop robustly during sensitive or critical period of early postnatal life, including cognition, language, music performance, sports, intelligence, thought, personality, and sociality in the case of human beings. Now we understand that the activity dependent synaptic circuit development is facilitated by glutamate receptor activation and subsequent calcium influx into postsynaptic neurons. However little is known about how calcium influx regulates competitive synaptic development. In this research project, we aimed to clarify this issue by focusing on calcium-dependent and-independent mechanisms using neuroanatomical, electrophysiological, and developmental biological technologies. Through this research project, I clarified that P/Q-type calcium channels promote the development and maturation of climbing fiber innervation to Purkinje cells in the cerebellum, while calcium-permeable glutamate receptors and transporters regulate synaptic circuit development in the somatosensory cortex. Moreover, the GluD2-Cbln1-neurexin system controls the connectivity of parallel fiber-Purkinje cell synapses to compete with climbing fiber innervation promoted by P/Q-type calcium channels.

Research Products

• [Journal Article] Cav2.1 in cerebellar Purkinje cells regulates competitive excitatory synaptic wiring, cell survival, and cerebellar biochemical compartmentalization (2012)
  • Author(s): Miyazaki T, Yamasaki M, Hashimoto K, Yamazaki M, Abe M, Usui H, Kano M, Sakimura K, Watanabe M
  • Journal Title: J. Neurosci Volume: 32 Pages: 1311-1328
  • Peer Reviewed
• [Journal Article] Developmental switching of perisomatic innervation from climbing fibers to basket cell fibers in cerebellar Purkinje cells (2011)
  • Author(s): Ichikawa R, Yamasaki M, Miyazaki T, Konno K, Hashimoto K, Tatsumi H, Inoue Y, Kano M, Watanabe M
  • Journal Title: J. Neurosci Volume: 31 Pages: 16916-16927
  • Peer Reviewed
• [Journal Article] Postsynaptic P/Q-type Ca2+ channels in cerebellar Purkinje cells mediate synaptic competition among multiple climbing fiber inputs during postnatal development (2011)
  • Author(s): Hashimoto K, Tsujita M, Miyazaki T, Kitamura K, Yamazaki M, Shin HS, Watanabe M, Sakimura K, Kano M
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 108 Pages: 9987-9992
  • Peer Reviewed
• [Journal Article] Modulation of postsynaptic kainate receptor function by auxiliary subunits. (2011)
  • Author(s): Straub C, Hunt DL Yamasaki M, Kim KS, Watanabe M, Castillo PE, Tomita S
  • Journal Title: Nat. Neurosci Volume: 14 Pages: 866-873
  • Peer Reviewed
• [Journal Article] Molecular and morphological configuration for 2-arachidonoylglycerol-mediated retrograde signaling at mossy cell-granule cell synapses in the dentate gyrus (2011)
  • Author(s): Uchigashima M, Yamazaki M, Yamasaki M, Tanimura A, Sakimura K, Kano M, Watanabe M
  • Journal Title: J. Neurosci Volume: 31 Pages: 7700-7714
  • Peer Reviewed
• [Journal Article] Unique inhibitory synapse with particularly rich endocannabinoid signaling machinery on pyramidal neurons in basal amygdaloid nucleus. (2011)
  • Author(s): Yoshida T, Uchigashima M, Yamasaki M, Katona I, Yamazaki M, Sakimura M, Kano M, Yoshioka M, Watanabe M
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 108 Pages: 3059-3064
  • Peer Reviewed
• [Journal Article] Cellular expression and subcellular localization of Secretogranin II in the mouse hippocampus and cerebellum. (2011)
  • Author(s): Miyazaki T, Yamasaki M, Uchigashima M, Matsushima A, Watanabe M
  • Journal Title: Eur. J. Neurosci Volume: 33 Pages: 82-94
  • Peer Reviewed
• [Journal Article] Glutamate receptor GluRd2 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] Ablation of glutamate receptor GluRd2 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] TARPs g-2 and g-7 are essential for AMPA receptor expression in the cerebellum. (2010)
  • Author(s): Yamazaki M, Fukaya M, Hashimoto K, Yamasaki M, Tsujita M, Itakura M, Abe M, Natsume R, Takahashi M, Kano M, Sakimura K, Watanabe M
  • Journal Title: Eur. J. Neurosci. Volume: 31 Pages: 2204-2220
  • Peer Reviewed
• [Journal Article] Preferential localization of muscarinic M1 receptor on dendritic shaft and spine of cortical pyramidal cells and its anatomical evidence for volume transmission. (2010)
  • Author(s): Yamasaki M, Matsui M, Watanabe M
  • Journal Title: J. Neurosci. Volume: 30 Pages: 4408-4418
• [Journal Article] Cbln1 is a ligand for an orphan glutamate receptor d2, a bidirectional synaptic organizer. (2010)
  • Author(s): Matsuda K, Miura E, Miyazaki T, Kakegawa W, Emi K, Narumi S, Fukazawa Y, Itoh-Ishida A, Kondo T, Shigemoto R, Watanabe M, Yuzaki M
  • Journal Title: Science Volume: 328 Pages: 363-368
  • Peer Reviewed
• [Journal Article] The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase a mediates retrograde suppression of synaptic transmission. (2010)
  • Author(s): Tanimura A, Yamazaki M, Hashimotodani Y, Uchigashima M, Kawata S, Abe M, Kita Y, Hashimoto K, Shimizu T, Watanabe M, Sakimura K, Kano M
  • Journal Title: Neuron Volume: 65 Pages: 320-32
  • Peer Reviewed
• [Journal Article] NMDA receptor GluN2B (GluRe2/NR2B) subunit Is crucial for channel function, postsynaptic macromolecular organization, and actin cytoskeleton at hippocampal CA3 synapses. (2009)
  • Author(s): Akashi K, Kakizaki T, Kamiya H, Fukaya M, Yamasaki M, Abe M, Natsume R, Watanabe M, Sakimura K
  • Journal Title: J. Neurosci Volume: 29 Pages: 10869-10882
  • Peer Reviewed
• [Journal Article] Translocation of a "winner" climbing fiber to the Purkinje cell dendrite and subsequent elimination of "losers" from the soma in developing cerebellum (2009)
  • Author(s): Hashimoto K, Ichikawa R, Kitamura K, Watanabe M, Kano M
  • Journal Title: Neuron Volume: 63 Pages: 106-118
  • Peer Reviewed
• [Journal Article] Cbln1 accumulates and colocalizes with Cbln3 and GluRd2 at parallel fiber-Purkinje cell synapses in the mouse cerebellum (2009)
  • Author(s): Miura E, Matsuda K, Morgan JI, Yuzaki M, Watanabe M
  • Journal Title: Eur. J. Neurosci. Volume: 29 Pages: 693-706
  • Peer Reviewed
• [Journal Article] Predominant expression of phospholipase Cb1 in telencephalic principal neurons and cerebellar interneurons, and its close allocation with related signaling molecules in somatodendritic neuronal elements (2008)
  • Author(s): Fukaya M, Uchigashima M, Nomura S, Hasegawa Y, Kikuchi H, Watanabe M
  • Journal Title: Eur. J. Neurosci. Volume: 28 Pages: 1744-1759
  • Peer Reviewed
• [Journal Article] Accumulation of AMPA receptors in autophagosomes in neuronal axons lacking adaptor protein AP4. (2008)
  • Author(s): Matsuda S, Miura E, Matsuda K, Kakegawa W, Kohda K, Watanabe M, Yuzaki M
  • Journal Title: Neuron Volume: 57 Pages: 730-745
  • Peer Reviewed
• [Journal Article] Cbln1 Regulates Rapid Formation and Maintenance of Excitatory Synapses in Mature Cerebellar Purkinje Cells in vitro and in vivo. (2008)
  • Author(s): Ito-Ishida A, Miura E, Emi K, Matsuda K, Iijima K, Narumi S, Kondo T, Kohda K, Watanabe M, Yuzaki M
  • Journal Title: J. Neurosci. Volume: 28 Pages: 5920-5930
  • Peer Reviewed
• [Journal Article] Glutamate transporters regulate lesion-induced period plasticity in the developing somatosensory cortex. (2008)
  • Author(s): Takasaki C, Okada R, Mitani A, Fukaya M, Yamasaki M, Fujihara Y, ShirakawaT, Tanaka K, Watanabe M.
  • Journal Title: J. Neurosci. Volume: 28 Pages: 4995-5006
  • Peer Reviewed
• [Journal Article] Axonal motility and its modulation by activity are branch-type specific in the intact adult cerebellum. (2007)
  • Author(s): Nishiyama H, Fukaya M, Watanabe M, Linden D
  • Journal Title: Neuron Volume: 56 Pages: 472-487
  • Peer Reviewed
• [Journal Article] Phospholipase CB3 is distributed in both somatodendritic and axonal compartments and localized around perisynapse and smooth endoplasmic reticulum in mouse Purkinje cell subsets. (2007)
  • Author(s): Nomura S, Fukaya M, Tsujioka T, Wu D, Watanabe M
  • Journal Title: Eur. J. Neurosci. Volume: 25 Pages: 659-672
  • Peer Reviewed
• [Journal Article] Subcellular arrangement of molecules for 2-arachidonoyl-glycerol-mediated retrograde signaling and its physiological contribution to synaptic modulation in the striatum. (2007)
  • Author(s): Uchigashima M, Narushima M, Fukaya M, Katona I, Kano M, Watanabe M
  • Journal Title: J. Neurosci. Volume: 27 Pages: 3663-3676
  • Peer Reviewed
• [Journal Article] GABAergic inhibition regulates developmental synapse elimination in the cerebellum
  • Author(s): 1 Nakayama H, Miyazaki T, Kitamura K, Hashimoto K, Yanagawa Y, Obata K, Sakimura K, Watanabe M, Kano M
  • Journal Title: Neuron Volume: (in press)
  • Peer Reviewed
• [Presentation] Glutamate transporter GLAST is essential for cytodifferentiation of Bergmann glia and maintenance of cerebellar excitatory wiring.小脳興奮性回路網維持とバーグマングリアの形態分化におけるグルタミン酸トランスポーターGLASTの機能的役割. (2011)
  • Author(s): Masahiko Watanabe.
  • Organizer: 第34回日本神経科学大会Neuro2011
  • Place of Presentation: パシフィコ横浜(神奈川)
  • Year and Date: 20110914-17
• [Presentation] Molecular and morphological configuration for 2-arachidonoylglycerol-mediated retrograde signaling at mossy cell-granule cell synapses in the dentate gyrus. (2011)
  • Author(s): Masahiko Watanabe
  • Organizer: 8th IBRO World Congress of Neuroscience.
  • Place of Presentation: Florence, Italy
  • Year and Date: 20110714-18
• [Book] 脳・神経科学入門講座 (2008)
  • Author(s): 渡辺雅彦
  • Total Pages: 190
  • Publisher: 改訂版、前編、羊土社
• [Book] 脳・神経科学入門講座 (2008)
  • Author(s): 渡辺雅彦
  • Total Pages: 173
  • Publisher: 改訂版、後編、羊土社
• [Remarks]
  • URL: http://www.med.hokudai.ac.jp/~anat-2w/