Circuit Formation Control Mechanisms by Excitation-Morphogenesis Coupling in the Developing Nervous System

• Project/Area Number: 19H01007
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 46:Neuroscience and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Bito Haruhiko 東京大学, 大学院医学系研究科(医学部), 教授 (00291964)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥45,760,000 (Direct Cost: ¥35,200,000、Indirect Cost: ¥10,560,000); Fiscal Year 2021: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000); Fiscal Year 2020: ¥14,040,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥3,240,000); Fiscal Year 2019: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000)
• Keywords: 脳・神経 / カルシウム / 脳発達 / 幼弱脳 / 発達

Outline of Research at the Start

本研究では、幼弱神経系における興奮形態形成連関による回路形成制御機構を解明するため、１）まず脳発達期におけるin vivo 幼弱神経系にて、L型Ca2+チャンネル依存的な新規Ca2+動員機構SRCaTが発生する時期・条件を解明し、さらに２）SRCaTの下流で興奮形態形成連関を担うCa2+/CaM伝達経路を明らかにし、引き続き、３）興奮形態形成連関により制御される神経回路形成ステップを同定する。

Outline of Final Research Achievements

We previously uncovered an L-type Ca2+ channel-dependent excitation-morphogenesis coupling mechanism SRCaT, which may contribute significantly to circuit formation during brain development. In this study, we attempt to elucidate some of the regulatory mechanisms mediated by SRCaT in the developing nervous system. We will 1) investigate the timing and conditions under which SRCaT occurs in the developing brain in vivo, 2) clarify the Ca2+ signal transduction pathway downstream of SRCaT, and 3) examine the mechanism potentially linking the disruption of SRCaT with the onset of autism-related animal phenotypes.

Academic Significance and Societal Importance of the Research Achievements

自閉スペクトラム症併発率70%のL型Ca2+チャンネル点変異によりSRCaTが破綻し、神経発達障害の一因とされる細胞移動異常が生じる。本研究は、このような表現型発見から逆に本研究により、自閉症関連動物表現型発症の本質的理解へ迫ろうとするものである。

Research Products

• [Journal Article] In utero electroporation and cranial window implantation for in vivo wide-field two-photon calcium imaging using G-CaMP9a transgenic mice. (2022)
  • Author(s): Sakamoto M, Ota K, Kondo Y, Okamura M, Fujii H, Bito H.
  • Journal Title: Star Protocols Volume: 3 Issue: 2 Pages: 101421-101421
  • DOI: 10.1016/j.xpro.2022.101421
  • Peer Reviewed / Open Access
• [Journal Article] A Flp-dependent G-CaMP9a transgenic mouse for neuronal imaging in?vivo (2022)
  • Author(s): Sakamoto Masayuki, Inoue Masatoshi, Takeuchi Atsuya, Kobari Shigetaka, Yokoyama Tatsushi, Horigane Shin-ichiro, Takemoto-Kimura Sayaka, Abe Manabu, Sakimura Kenji, Kano Masanobu, Kitamura Kazuo, Fujii Hajime, Bito Haruhiko
  • Journal Title: Cell Reports Methods Volume: 2 Issue: 2 Pages: 100168-100168
  • DOI: 10.1016/j.crmeth.2022.100168
  • Peer Reviewed / Open Access
• [Journal Article] Identification of ultra-rare disruptive variants in voltage-gated calcium channel-encoding genes in Japanese samples of schizophrenia and autism spectrum disorder (2022)
  • Author(s): Wang C, Horigane SI, Wakamori M, Ueda S, Kawabata T, Fujii H, Kushima I, Kimura H, Ishizuka K, Nakamura Y, Iwayama Y, Ikeda M, Iwata N, Okada T, Aleksic B, Mori D, Yoshida T, Bito H, Yoshikawa T, Takemoto-Kimura S, Ozaki N
  • Journal Title: Translational Psychiatry Volume: 12 Issue: 1 Pages: 84-84
  • DOI: 10.1038/s41398-022-01851-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of an L-type Ca 2+ channel-dependent Ca 2+ transient during the radial migration of cortical excitatory neurons (2020)
  • Author(s): Horigane S, Hamada S, Kamijo S, Yamada H, Yamasaki M, Watanabe M, Bito H, Ohtsuka T, Takemoto-Kimura S
  • Journal Title: Neurosci Res Volume: S0168-0102(20)30391-6 Pages: 30391-6
  • DOI: 10.1016/j.neures.2020.06.003
  • Peer Reviewed / Open Access
• [Journal Article] Rational engineering of XCaMPs, a multicolor GECI suite for in vivo imaging of complex brain circuit dynamics. (2019)
  • Author(s): Inoue M, Takeuchi A, Manita S, Horigane S-i, Sakamoto M, Kawakami R, Yamaguchi K, Otomo K, Yokoyama H, Kim R, Yokoyama T, Takemoto-Kimura S, Abe M, Okamura M, Kondo Y, Quirin S, Ramakrishnan C, Imamura T, Sakimura K, Nemoto T, Kano M, Fujii H, Deisseroth K, Kitamura K, Bito H.
  • Journal Title: Cell Volume: 177 Issue: 5 Pages: 1346-1360
  • DOI: 10.1016/j.cell.2019.04.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Multiplex imaging of neural activity and signaling dynamics (2022)
  • Author(s): Bito H.
  • Organizer: Biennial Meeting of the International Society for Neurochemistry -held in conjunction with the Asian-Pacific Society for Neurochemistry
  • Int'l Joint Research / Invited
• [Presentation] Plasticity and memory mechanisms in vivo. (2020)
  • Author(s): Bito H
  • Organizer: tockholm Trio - University of Tokyo Strategic Partnership Workshop
  • Int'l Joint Research / Invited
• [Presentation] Lessons learned from elucidating calcium-dependent neural circuit control mechanisms. (2020)
  • Author(s): Bito H
  • Organizer: Japanese Pharmacology Society Annual Meeting
  • Invited
• [Presentation] Rational engineering of XCaMPs, a next-generation Ca2+ indicator. (2019)
  • Author(s): Bito H
  • Organizer: 14th International Conference of Neurons and Brain Diseases, Queenstown, New Zealand
  • Int'l Joint Research / Invited