Molecular basis of functional neural circuits of excitatory and inhibitory neurons in the cerebral cortex

• Project/Area Number: 17K01976
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Basic / Social brain science
• Research Institution: The University of Tokushima (2018-2021); Osaka University (2017)
• Principal Investigator: HIRAYAMA Teruyoshi 徳島大学, 大学院医歯薬学研究部(医学域), 准教授 (40437398)
• Project Period (FY): 2017-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 大脳皮質 / 神経回路 / 抑制性神経細胞 / 神経発生 / 神経細胞 / 遺伝子改変マウス / 神経科学 / 脳神経疾患 / 発生・分化

Outline of Final Research Achievements

I generated and analyzed mice lacking CTCF （CTCF-cKO）specifically in inhibitory neurons in the cerebral cortex. CTCF-cKO mice exhibited epileptic-like symptoms and died within the first month after birth. Physiological analysis revealed a significant expansion of the response area of somatosensory cortex in response to stimuli. These results suggested that inhibitory neurons in CTCF-cKO were unable to adequately suppress excitatory activity. In addition, the distribution of inhibitory neurons in the cerebral cortex showed differences compared to the control mice. The same analysis was performed for the c-Pcdh gene group, and we found similar results.

Academic Significance and Societal Importance of the Research Achievements

大脳皮質の興奮性細胞と抑制性細胞は別々の場所で産生され、大脳皮質で統合されて機能的神経回路として働くことが知られているが、その分子基盤は不明である。また、抑制性の神経細胞は、大脳皮質では散在的に分布するが、その分子基盤も不明である。本研究成果は、これらの分子基盤としてc-Pcdh 遺伝子群とその発現制御分子であるCTCFが働いていることを示唆する。興奮性細胞と抑制性細胞のバランスは機能的な神経回路形成に重要であり、バランスが崩れると様々な神経疾患の原因となり得るため、本研究成果は、これらの分子メカニズムを解明するのに重要な知見を与える。

Research Products

• [Int'l Joint Research] McLean Hospital/Harvard Medical School/New York Medical College(米国)
• [Journal Article] Suppression of DNA Double-Strand Break Formation by DNA Polymerase β in Active DNA Demethylation Is Required for Development of Hippocampal Pyramidal Neurons (2020)
  • Author(s): Uyeda A, Onishi K, Hirayama T, Hattori S, Miyakawa T, Yagi T, Yamamoto N, Sugo N.
  • Journal Title: J Neurosci. Volume: 40 Issue: 47 Pages: 9012-9027
  • DOI: 10.1523/jneurosci.0319-20.2020
  • Peer Reviewed
• [Journal Article] Pcdhb deficiency affects hippocampal CA1 ensemble activity and contextual fear discrimination (2020)
  • Author(s): Asai H, Ohkawa N, Saitoh Y, Ghandour K, Murayama E, Nishizono H, Matsuo M, Hirayama T, Kaneko R, Muramatsu S, Yagi T, Inokuchi K
  • Journal Title: Molecular Brai Volume: 13 Issue: 1 Pages: 7-7
  • DOI: 10.1186/s13041-020-0547-z
  • Peer Reviewed / Open Access
• [Journal Article] Snf2h Drives Chromatin Remodeling to Prime Upper Layer Cortical Neuron Development (2019)
  • Author(s): Alvarez-Saavedra Mat?as、Yan Keqin、De Repentigny Yves、Hashem Lukas E.、Chaudary Nidhi、Sarwar Shihab、Yang Doo、Ioshikhes Ilya、Kothary Rashmi、Hirayama Teruyoshi、Yagi Takeshi、Picketts David J.
  • Journal Title: Frontiers in Molecular Neuroscience Volume: 12 Pages: 243-243
  • DOI: 10.3389/fnmol.2019.00243
  • NAID: 120006956843
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dysregulated protocadherin-pathway activity as an intrinsic defect in iPSC-derived cortical interneurons from patients with schizophrenia (2019)
  • Author(s): Shao Z. et al. (Hirayama T.含め、著者20名以上)
  • Journal Title: Nature Neurosci. Volume: 22(2) Issue: 2 Pages: 229-242
  • DOI: 10.1038/s41593-018-0313-z
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genome Stability by DNA polymerase β in Neural Progenitors Contributes Neuronal Differentiation in Cortical Development (2017)
  • Author(s): Kohei Onishi, Akiko Uyeda, Mistuhiro Shida, Teruyoshi Hirayama, Takeshi Yagi, Nobuhiko Yamamoto, Noriyuki Sugo
  • Journal Title: Journal of Neuroscience Volume: 37 Issue: 35 Pages: 8444-8485
  • DOI: 10.1523/jneurosci.0665-17.2017
  • Peer Reviewed
• [Journal Article] The methyltransferase SETDB1 regulates a large neuron- specific topological chromatin domain. (2017)
  • Author(s): Jiang Y, Loh YE, Rajarajan P, Hirayama T, Liao W, Kassim BS, Javidfar B, Hartley BJ, Kleofas L, Park RB, Labonte B, Ho SM, Chandrasekaran S, Do C, Ramirez BR, Peter CJ, C W JT, Safaie BM, Morishita H, Roussos P, Nestler EJ, Schaefer A, Tycko B, Brennand KJ, Yagi T, Shen L, Akbarian S.
  • Journal Title: Nature Genetics Volume: 49 Issue: 8 Pages: 1239-1250
  • DOI: 10.1038/ng.3906
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Deletion of cPcdhs affects cell ensemble activities in the hippocampus (2019)
  • Author(s): Hirotaka Asai, Noriaki Ohkawa, Yoshito Saitoh, Khaled Gandour1, Hirofumi Nishizono, Mina Matsuo, Teruyoshi Hirayama, Shin-ich Muramatsu, Takeshi Yagi, and Kaoru Inokuchi
  • Organizer: NEURO2019
• [Presentation] 嗅神経回路形成におけるクラスター型プロトカドヘリンの機能解析 (2019)
  • Author(s): 本間 貴裕、平山 晃斉、三宝 誠、平林 真澄、八木 健
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] クラスター型プロトカドヘリンγは抑制性神経細胞の生存に関与する (2018)
  • Author(s): 佐藤 李奈、平山 晃斉、足澤 悦子、河村 菜々実、熊谷 牧子、有賀 理瑛、吉武 講平、吉村 由美子、澁木 克栄、八木 健
  • Organizer: 第41回日本分子生物学会年会