Generation and analysis of novel Reln-deleted mouse model corresponding to exonic Reln deletion in schizophrenia

• Project/Area Number: 19K07384
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Nagoya University
• Principal Investigator: MORI DAISUKE 名古屋大学, 脳とこころの研究センター(医), 特任准教授 (00381997)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 統合失調症 / リーリン / モデルマウス / Reln欠失 / 精神疾患モデルマウス / リーリン遺伝子 / 動物モデル / 遺伝子改変マウス

Outline of Research at the Start

リーリンは脳の発生・成熟・維持に関与するタンパク質である。ゲノム編集技術によって当該リーリン欠失をモデルとした患者型リーリン遺伝子欠失マウスを新規で作製した。本研究課題では、リーリン欠失マウスの行動薬理学的解析、組織病理学的解析、培養神経細胞を用いたin vitro遊走解析、リーリンシグナル伝達の分子生物学的解析、遺伝子発現解析を実施する。リーリン欠失患者由来iPS細胞から分化させて認められたような細胞遊走およびリーリンシグナル異常が生じているかどうかを比較し、リーリン欠失から統合失調症発症に到る機構解明を目指す。

Outline of Final Research Achievements

The phenotype of homozygous Reln-del mice was similar to that of reeler mice with cerebellar atrophy, dysplasia of the cerebral layers, and abrogated protein levels of cerebral reelin. The expression of reelin in heterozygous Reln-del mice was approximately half of that in wild-type mice. Conversely, behavioral analyses in heterozygous Reln-del mice without cerebellar atrophy or dysplasia showed abnormal social novelty in the three-chamber social interaction test. In vitro reaggregation formation and neuronal migration were severely altered in the cerebellar cultures of homozygous Reln-del mice.

Academic Significance and Societal Importance of the Research Achievements

多くの研究により報告されているReln変異マウスの行動変化には、統合失調症に似た表現型が見られた。加えてReln欠失統合失調症患者を同定し、iPS細胞の樹立から神経細胞移動の方向性異常を見出すことができた。Reln欠失マウスとReln欠失iPS細胞の相互解析からリーリン欠失を介した統合失調症の病態メカニズムを明らかにし、創薬につなげる礎となる可能性がある。

Research Products

• [Journal Article] Sensory evaluation of the bitterness of asenapine using D-sorbitol pretreatment: single-blind, placebo-controlled, crossover trial (2023)
  • Author(s): Wada S, Iwamoto K, Okumura H, Hida H, Hiraoka S, Kamei A, Mori D, Yamada K, Ozaki N
  • Journal Title: BMC Psychiatry Volume: 23 Issue: 1 Pages: 159-159
  • DOI: 10.1186/s12888-023-04664-5
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of Rho-kinase ameliorates decreased spine density in the medial prefrontal cortex and methamphetamine-induced cognitive dysfunction in mice carrying schizophrenia-associated mutations of the Arhgap10 gene. (2023)
  • Author(s): Tanaka R, Liao J, Hada K, Mori D, Nagai T, Matsuzaki T, Nabeshima T, Kaibuchi K, Ozaki N, Mizoguchi H, Yamada K.
  • Journal Title: Pharmacological Research Volume: 187 Pages: 106589-106589
  • DOI: 10.1016/j.phrs.2022.106589
  • Peer Reviewed / Open Access
• [Journal Article] Cross-disorder analysis of genetic and regulatory copy number variations in bipolar disorder, schizophrenia, and autism spectrum disorder (2022)
  • Author(s): Kushima Itaru、Nakatochi Masahiro、Aleksic Branko、Okada Takashi、（中略）、Ozaki Norio
  • Journal Title: Biological Psychiatry Volume: - Issue: 5 Pages: 362-374
  • DOI: 10.1016/j.biopsych.2022.04.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Establishment of induced pluripotent stem cells from a patient with 16p13.11 duplication and VPS13B deletion (2022)
  • Author(s): Okumura, H. Arioka, Y. Kushima, I. Mori, D. Ozaki, N.
  • Journal Title: Stem Cell Res Volume: 64 Pages: 102884-102884
  • DOI: 10.1016/j.scr.2022.102884
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of Reelin signaling and neurodevelopmental trajectory in primary cultured cortical neurons with RELN deletion identified in schizophrenia (2021)
  • Author(s): Tsuneura Yumi、Sawahata Masahito、Itoh Norimichi、Miyajima Ryoya、Mori Daisuke、Kohno Takao、Hattori Mitsuharu、Sobue Akira、Nagai Taku、Mizoguchi Hiroyuki、Nabeshima Toshitaka、Ozaki Norio、Yamada Kiyofumi
  • Journal Title: Neurochemistry International Volume: 144 Pages: 104954-104954
  • DOI: 10.1016/j.neuint.2020.104954
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Generation and analysis of novel Reln-deleted mouse model corresponding to exonic Reln deletion in schizophrenia (2020)
  • Author(s): Masahito Sawahata, Daisuke Mori, Yuko Arioka, Hisako Kubo, Itaru Kushima, Kanako Kitagawa, Akira Sobue, Emiko Shishido, Mariko Sekiguchi, Akiko Kodama, Ryosuke Ikeda, Branko Aleksic, Hiroki Kimura, Kanako Ishizuka, Taku Nagai, Kozo Kaibuchi, Toshitaka Nabeshima, Kiyofumi Yamada, Norio Ozaki
  • Journal Title: Psychiatry and clinical neurosciences Volume: 1 Issue: 5 Pages: 1-10
  • DOI: 10.1111/pcn.12993
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 3q29 欠失統合失調症モデルマウスの活動リズムの解析 (2021)
  • Author(s): Daisuke Mori, Takashi Hirao, Ryosuke Ikeda, Yuko Arioka, Itaru Kushima, Norio Ozaki
  • Organizer: 日本神経科学学会
  • Int'l Joint Research