Role of activity-dependent gene Arc in synaptic plasticity

• Project/Area Number: 24300117
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Neuroscience in general
• Research Institution: Kyoto University (2013-2014); The University of Tokyo (2012)
• Principal Investigator: OKUNO Hiroyuki 京都大学, 医学(系)研究科(研究院), 特定准教授 (80272417)
• Co-Investigator(Renkei-kenkyūsha): BITO Haruhiko 東京大学, 大学院医学系研究科, 教授 (00291964) ; SAKIMURA Kenji 新潟大学, 脳研究所, 教授 (40162325)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥19,240,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥4,440,000); Fiscal Year 2014: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2013: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2012: ¥10,140,000 (Direct Cost: ¥7,800,000、Indirect Cost: ¥2,340,000)
• Keywords: シナプス / 長期記憶 / 海馬 / Arc / CaMKII / 活動依存的遺伝子発現 / 可塑性 / 神経科学 / 脳・神経 / 遺伝子 / シグナル伝達

Outline of Final Research Achievements

Long-term synaptic plasticity and memory formation require activity-dependent gene expression. However, it remains unknown how such activity-induced gene products are targeted to proper cellular compartments including synapses. In the present study, we investigated the targeting of the memory related-protein Arc from the soma to the synapses, and elucidated a novel “inverse” synaptic tagging mechanism that enables Arc to specifically target the un-potentiated synapses. The findings provide new mechanistic insights into how the contrast between strong and weak synapses is maintained during long-term synaptic plasticity. We further identified the CREB coactivator CRTC1 as a critical factor for Arc expression as well as memory function.

Research Products

• [Journal Article] Neuromodulatory effect of Gαs- or Gαq-coupled G-protein-coupled receptor on NMDA receptor selectively activates the NMDA receptor/Ca2+/calcineurin/cAMP response element-binding protein-regulated transcriptional coactivator 1 pathway to effectively induce brain-derived neurotrophic factor expression in neurons. (2015)
  • Author(s): Fukuchi M, Tabuchi A, Kuwana Y, Watanabe S, Inoue M, Takasaki I, Izumi H, Tanaka A, Inoue R, Mori H, Komatsu H, Takamori H, Okuno H, Bito H, Tsuda M.
  • Journal Title: The Journal of Neuroscience Volume: 35 Pages: 5606-5624
  • DOI: 10.1523/jneurosci.3650-14.2015
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Class I Histone deacetylase-mediated repression of the proximal promoter of the activity-regulated cytoskeleton-associated protein gene regulates its response to brain-derived neurotrophic factor. (2015)
  • Author(s): Fukuchi M, Nakashima F, Tabuchi A, Shimotori M, Tatsumi S, Okuno H, Bito H, Tsuda M
  • Journal Title: The Journal of Biological Chemistry Volume: 290 Pages: 6825-36
  • DOI: 10.1074/jbc.m114.617258
  • Peer Reviewed / Open Access
• [Journal Article] Whole-brain mapping of behaviourally induced neural activation in mice. (2015)
  • Author(s): Vousden DA, Epp J, Okuno H, Nieman BJ, van Eede M, Dazai J, Ragan T, Bito H, Frankland PW, Lerch JP, Henkelman RM.
  • Journal Title: Brain Struct Funct. Volume: 220 Pages: 2043-2057
  • DOI: 10.1007/s00429-014-0774-0
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Region-Specific Activation of CRTC1-CREB Signaling Mediates Long-Term Fear Memory (2014)
  • Author(s): Nonaka M, Kim R, Fukushima H, Sasaki K, Suzuki K, Okamura M, Ishii Y, Kawashima T, Kamijo S, Takemoto-Kimura S, Okuno H, Kida S, Bito H
  • Journal Title: Ｎｅｕｒｏｎ Volume: 84 Pages: 92-106
  • DOI: 10.1016/j.neuron.2014.08.049
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A new era for functional labeling of neurons: activity-dependent promoters have come of age (2014)
  • Author(s): Kawashima T, Okuno H, Bito H
  • Journal Title: Front. Neural Circuits Volume: 8 Pages: 37-37
  • DOI: 10.3389/fncir.2014.00037
  • Peer Reviewed / Open Access
• [Journal Article] 核からシナプスへの分子ターゲティング機構の解明‐神経回路の長期可塑性を制御するArcタンパク質のケーススタディー (2014)
  • Author(s): 奥野浩行、尾藤晴彦
  • Journal Title: 生化学 Volume: 86 Pages: 18-27
• [Journal Article] Functional labeling of neurons and their projections using a synthetic activity-dependent promoter E-SARE. (2013)
  • Author(s): Kawashima T, Kitamura K, Suzuki K, Nonaka M, Kamijo S, Takemoto-Kimura S, Kano M, Okuno H, Ohki K, Bito H.
  • Journal Title: Nat. Methods Volume: 10 Pages: 889-895
  • DOI: 10.1038/nmeth.2559
  • Peer Reviewed
• [Journal Article] Arc/Arg3.1 is a postsynaptic mediator of activity-dependent synapse elimination in the developing cerebellum. (2013)
  • Author(s): Mikuni et al.
  • Journal Title: Neuron Volume: 78 Pages: 1024-1035
  • DOI: 10.1016/j.neuron.2013.04.036
  • Peer Reviewed
• [Journal Article] Nonlinear decoding and asymmetric representation of neuronal input information by CaMKIIa and calcineurin (2013)
  • Author(s): Fujii H, Inoue M, Okuno H, Sano Y; Takemoto-Kimura S, Kitamura K, Kano M, Bito H.
  • Journal Title: Cell Rep. Volume: 3(印刷中)(掲載確定) Pages: 978-87
  • DOI: 10.1016/j.celrep.2013.03.033
  • Peer Reviewed
• [Journal Article] Untangling the two-way signalling route from synapses to the nucleus, and from the nucleus back to the synapses. (2013)
  • Author(s): Nonaka et al.
  • Journal Title: Philos Trans R Soc Lond B Biol Sci. Volume: 369
  • DOI: 10.1098/rstb.2013.0150
  • Peer Reviewed
• [Journal Article] Inverse synaptic tagging of inactive synapses via dynamic interaction of Arc/Arg3.1 with CaMKII s (2012)
  • Author(s): 奥野浩行, 他
  • Journal Title: Commun. Integr. Biol. Volume: 149 Pages: 496-498
  • DOI: 10.1016/j.cell.2012.02.062
  • Peer Reviewed
• [Journal Article] Visualization of the cortical projection neurons by retrograde TET-Off lentiviral vector (2012)
  • Author(s): 渡我部昭哉, 他
  • Journal Title: PLoS ONE Volume: 7
  • DOI: 10.1371/journal.pone.0046157
  • Peer Reviewed
• [Journal Article] Executive function deficits and low social dominance in mice exposed to a low dose of dioxin in utero and via lactation. (2012)
  • Author(s): Endo T, Kakeyama M, Uemura Y, Haijima A, Okuno H, Bito H, Tohyama C
  • Journal Title: PlosOne Volume: 7
  • DOI: 10.1371/journal.pone.0050741
  • Peer Reviewed
• [Presentation] 神経特異的前初期遺伝子Arcによる認知機能調節 (2014)
  • Author(s): 奥野 浩行
  • Organizer: 包括脳2014冬のシンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2014-12-13
  • Invited
• [Presentation] Regulation of synaptic and cognitive function through the activity-dependent gene Arc/Arg3.1. (2014)
  • Author(s): Okuno, H., Endo, T., Kim, R., Ishii, Y., Minatohara, K., Araki, A., Sakimura, K., Bito, H.
  • Organizer: 第36回日本生物学的精神医学会・第57回日本神経化学学会
  • Place of Presentation: 奈良
  • Year and Date: 2014-09-29
  • Invited
• [Presentation] Arc's roles in inverse synaptic tagging and memory formation. (2014)
  • Author(s): Okuno, H., Minatohara, K., Masuda, H.
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-11
  • Invited
• [Presentation] Inverse synaptic tagging : a new mechanism for late-phase synaptic plasticity. (2012)
  • Author(s): Okuno H, Ishii Y, Kawashima T, Nonaka M, Akashi K, Sakimura K, Bito H.
  • Organizer: 第35回日本分子生物年会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡(福岡市)
  • Year and Date: 2012-12-11
• [Presentation] Visualization of an active ensemble of cortical neurons in vivo using a novel activity-dependent promoter E-SARE. (2012)
  • Author(s): Kawashimna T, Kitamura K, Ohki K, Suzuki K, Nonaka M, Kamijo S, Takemoto-Kimura S, Kano M, Okuno H, Bito H.
  • Organizer: 42th Annual Meeting of Soc for Neurosci,
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2012-10-15
• [Presentation] Possible involvement of the Ca2+-dependent gene Arc in activity dependent synapse elimination in the cerebellum. (2012)
  • Author(s): Mikuni T, Uesaka N, Okuno H, Hirai H, Bito H, Kano M
  • Organizer: 42th Annual Meeting of Soc for Neurosci
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2012-10-14
• [Presentation] The role of Arc in inverse tagging of inactive synapses
  • Author(s): Okuno, H
  • Organizer: International Society for Neurochemistry (ISN2013)
  • Place of Presentation: Cancun, Mexico
  • Invited
• [Presentation] Regulation of synaptic strength byArc/Arg3.1-CaMKIIbeta interaction through inverse tagging process
  • Author(s): Okuno, H
  • Organizer: Korean Physiology Society (KPS 2013)
  • Place of Presentation: Seoul, South Korea
  • Invited
• [Presentation] Ca2+/カルモジュリン依存性キナーゼIIβとArcによるAMPA型グルタミン酸受容体の量的制御
  • Author(s): 奥野浩行、石井雄一郎、川島尚之、野中美応、明石馨、崎村建司、尾藤晴彦
  • Organizer: 第36回日本分子生物年会
  • Place of Presentation: 神戸国際展示場（神戸市）
  • Invited
• [Book] Neuroplasticity in "Homeostatic control of brain function” eds., Masino, SA. & Boison, (2015)
  • Author(s): Okuno, H.
  • Publisher: Oxford University Press
• [Book] Inverse synaptic tagging by Arc. in "Novel Mechanisms of Memory" eds., Giese, K.P. & Radwanska, K., (2015)
  • Author(s): Okuno, H., Araki, A., Minatohara, K.
  • Publisher: Springer
• [Book] Selected key areas for future research on the claustrum. in “The Claustrum” eds., Smythies., Edelstein L., & Ramachandran, V.S. (2014)
  • Author(s): Okuno, H., Smythies, J., Edelstein L.
  • Total Pages: 13
  • Publisher: Elsevier
• [Book] Chapter "Selected key areas for future research on the claustrum" in The Claustrum (2013)
  • Author(s): Okuno, Smythies and Edelstein
  • Publisher: Academia Press