微細な組織構築変化をマイクロエンドフェノタイプとする精神神経疾患の病態解明

• Project Area: Unraveling micro-endophenotypes of psychiatric disorders at the molecular, cellular and circuit levels.
• Project/Area Number: 15H01293
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Keio University
• Principal Investigator: 久保 健一郎 慶應義塾大学, 医学部(信濃町), 講師 (20348791)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000); Fiscal Year 2016: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2015: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
• Keywords: マイクロエンドフェノタイプ / 脳組織構築 / モデルマウス / 神経細胞移動 / 虚血 / 大脳皮質 / 発生 / リーリン / 子宮内電気穿孔法 / 組織構築

Outline of Annual Research Achievements

本年度は、マイクロエンドフェノタイプとしての微細な脳組織構築の変化を持つ動物モデルとして、我々が確立した胎児期の代表的な環境要因である胎仔期虚血モデルマウス、異所性皮質モデルマウスを用いて、微細な脳組織構築の変化がどのように脳機能に影響を与えて病態に関与するのか、その病態メカニズムの解明を行った。
特に、胎仔期虚血モデルマウスにおいては、脳の組織学的な解析に際して、子宮内エレクトロポレーション法を用いることにより、緑色蛍光タンパク質（GFP）などの蛍光タンパク質を神経細胞に導入して、虚血性脳障害による影響の解析を行った。正常対照において移動が終了する状態においても虚血が誘導されたマウスではまだ移動中の神経細胞を数多く認めた。これらの神経細胞は最終的には脳表面近くに移動する細胞が多数を占めたものの、最終的な神経細胞が配置される位置には変化を認めた。また、神経回路網における変化も認めた。
また、胎仔期虚血モデルマウスの行動解析に際しては、子宮内エレクトロポレーション法を用いる際に、緑色蛍光タンパク質（GFP）などの蛍光タンパク質のみならず、人工受容体を発現するプラスミドを神経細胞に導入して、DREDD（Designer Receptors Exclusively Activated by Designer Drugs）システムを用いた神経活動操作を行った。生後にクロザピンNオキサイド（CNO）を投与して、人工受容体を発現する神経細胞に特異的な神経活動活性化を行った。胎仔期虚血モデルマウスは、Y字迷路試験において正常対照マウスと比較した際に有意な低下をみとめ作業記憶の障害が示唆されたため、人為的に神経細胞の活動を変化させることによって低下した作業記憶が改善するかどうかの検証を行った。その結果、前頭前皮質の活性化を行うと、低下した作業記憶が有意に改善することが明らかになった。

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] Baylor College of Medicine/Johns Hopkins Univ. School of Medicine(米国)
• [Journal Article] Association of impaired neuronal migration with cognitive deficits in extremely preterm infants (2017)
  • Author(s): K. Kubo, K. Deguchi, T. Nagai, Y. Ito, K. Yoshida, T. Endo, S. Benner, W.Shan, A.o Kitazawa, M. Aramaki, K. Ishii, M. Shin, Y. Matsunaga, K. Hayashi, M. Kakeyama, C. Tohyama, K. F. Tanaka, K. Tanaka, S. Takashima, M. Nakayama, M. Itoh, Y. Hirata, B. Antalffy, D. D. Armstrong, K.Yamada, K. Inoue, and K. Nakajima
  • Journal Title: JCI Insight Volume: 印刷中
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] ApoER2 controls not only neuronal migration in the intermediate zone, but also termination of migration in the developing cerebral cortex (2017)
  • Author(s): Yuki Hirota, Ken-ichiro Kubo, Takahiro Fujino, Tokuo T. Yamamoto, and Kazunori Nakajima
  • Journal Title: Cereb. Cortex Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Excessive activation of AhR signaling disrupts neuronal migration in the hippocampal CA1 region in the developing mouse (2017)
  • Author(s): Eiki Kimura, Ken-ichiro Kubo, Toshihiro Endo, Kazunori Nakajima, Masaki Kakeyama, and Chiharu Tohyama
  • Journal Title: The Journal of Toxicological Sciences Volume: 42 Issue: 1 Pages: 25-30
  • DOI: 10.2131/jts.42.25
  • NAID: 130005286645
  • ISSN: 0388-1350, 1880-3989
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Reelin transiently promotes N-cadherin-dependent neuronal adhesion during mouse cortical development (2017)
  • Author(s): Yuki Matsunaga, Mariko Noda, Hideki Murakawa, Kanehiro Hayashi, Arata Nagasaka, Seika Inoue, Takaki Miyata, Takashi Miura, Ken-ichiro Kubo, and Kazunori Nakajima
  • Journal Title: Proc. Natl. Acad. Sci. U.S.A. Volume: 114 Issue: 8 Pages: 2048-2053
  • DOI: 10.1073/pnas.1615215114
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Reelin and neuropsychiatric disorders (2016)
  • Author(s): Kazuhiro Ishii, Ken-ichiro Kubo, and Kazunori Nakajima
  • Journal Title: Front. Cell. Neurosci. Volume: 10
  • DOI: 10.3389/fncel.2016.00229
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] SUMOylation of DISC1: a potential role in neural progenitor proliferation in the developing cortex. (2016)
  • Author(s): Stephanie Tankou, Kazuhiro Ishii, Christina Elliott, Krishna C. Yalla, Jon P. Day, Keiko Furukori, Ken-ichiro Kubo, Nicholas J. Brandon, Qiyi Tang, Gary Hayward, Kazunori Nakajima, Miles D. Houslay, Atsushi Kamiya, George Baillie, Koko Ishizuka, and Akira Sawa
  • Journal Title: Mol. Neuropsychiatry Volume: 2 Issue: 1 Pages: 20-27
  • DOI: 10.1159/000444257
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] DISC1 a key molecular lead in psychiatry and neurodevelopment: No-More Disrupted-in-Schizophrenia. (2016)
  • Author(s): Minae Niwa, Tyler Cash-Padgett, Ken-Ichiro Kubo, Atsushi Saito, Kazuhiro Ishii, Akiko Sumitomo, Yu Taniguchi, Koko Ishizuka, Hanna Jaaro-Peled, Toshifumi Tomoda, Kazunori Nakajima, Akira Sawa, and Atsushi Kamiya
  • Journal Title: Mol. Psychiatry Volume: 21 Issue: 11 Pages: 1488-1489
  • DOI: 10.1038/mp.2016.154
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] In utero bisphenol A exposure induces abnormal neuronal migration in the cerebral cortex of mice. (2016)
  • Author(s): Wenting Ling, Toshihiro Endo, Ken-ichiro Kubo, Masaki Kakeyama, Kazunori Nakajima, and Chiharu Tohyama.
  • Journal Title: Front. Endocrinol. Volume: 7 Pages: 7-7
  • DOI: 10.3389/fendo.2016.00007
  • Peer Reviewed / Open Access
• [Journal Article] Neuronal heterotopias affect the activities of distant brain areas and lead to behavioral deficits (2015)
  • Author(s): Kazuhiro Ishii, Ken-ichiro Kubo, Toshihiro Endo, Keitaro Yoshida, Seico Benner, Yukiko Ito, Hidenori Aizawa, Michihiko Aramaki, Akihiro Yamanaka, Kohichi Tanaka, Norio Takata, Kenji Tanaka, Masaru Mimura, Chiahru Tohyama, Masaki Kakeyama, and Kazunori Nakajima
  • Journal Title: Journal of Neuroscience Volume: 35 Issue: 36 Pages: 12432-45
  • DOI: 10.1523/jneurosci.3648-14.2015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The COUP-TFII/Neuropilin-2 is a molecular switch steering diencephalon-derived GABAergic neurons in the developing mouse brain (2015)
  • Author(s): Shigeaki Kanatani, Takao Honda, Michihiko Aramaki, Kanehiro Hayashi, Ken-ichiro Kubo, Mami Ishida, Daisuke H. Tanaka, Takeshi Kawauchi, Katsutoshi Sekine, Sayaka Kusuzawa, Takahiko Kawasaki, Tatsumi Hirata, Hidenori Tabata, Per Uhlen and Kazunori Nakajima
  • Journal Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 112(36) Issue: 36
  • DOI: 10.1073/pnas.1420701112
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Cellular dynamics of neuronal migration in the hippocampus. (2015)
  • Author(s): Hayashi K, Kubo K, Kitazawa A and Nakajima K
  • Journal Title: Front.Neurosci Volume: in press Pages: 135-135
  • DOI: 10.3389/fnins.2015.00135
  • Peer Reviewed / Open Access
• [Journal Article] Reelin has a preventive effect on phencyclidine-induced cognitive and sensory-motor gating deficits. (2015)
  • Author(s): Ishii K, Nagai T, Hirota Y, Noda M, Nabeshima T, Yamada K, Kubo K, Nakajima K.
  • Journal Title: Neurosci Res. Volume: 96 Pages: 30-36
  • Peer Reviewed
• [Journal Article] Developmental origin of abnormal dendritic growth in the mouse brain induced by in utero disruption of aryl hydrocarbon receptor signaling. (2015)
  • Author(s): Eiki Kimura, Ken-ichiro Kubo, Chieri Matsuyoshi, Seico Benner, Mayuko Hosokawa, Toshihiro Endo, Wenting Ling, Masanobu Kohda, Kazuhito Yokoyama, Kazunori Nakajima, Masaki Kakeyama, and Chiharu Tohyama.
  • Journal Title: Neurotoxicol. Teratol. Volume: 52 Pages: 42-50
  • DOI: 10.1016/j.ntt.2015.10.005
  • Peer Reviewed / Open Access
• [Presentation] 超早産児脳障害のモデルマウス脳における組織構築の解析 (2017)
  • Author(s): 久保健一郎、出口貴美子、北澤彩子、石井一裕、シン ミンギョン、高嶋幸男、中山雅弘、伊藤雅之、井上健、仲嶋一範
  • Organizer: 第122回日本解剖学会総会・全国学術集会
  • Place of Presentation: 長崎大学坂本キャンパス、長崎市(長崎県)
  • Year and Date: 2017-03-28
• [Presentation] 哺乳類大脳皮質発生における神経細胞移動の領野別検討 (2017)
  • Author(s): 吉永怜史、北澤彩子、シン ミンギョン、久保健一郎、仲嶋一範
  • Organizer: 第122回日本解剖学会総会・全国学術集会
  • Place of Presentation: 長崎大学坂本キャンパス、長崎市(長崎県)
  • Year and Date: 2017-03-28
• [Presentation] Why does cognitive impairment frequently develop later in extremely preterm infants (2016)
  • Author(s): Ken-ichiro Kubo, Kimiko Deguchi, Taku Nagai, Wei Shan, Ayako Kitazawa, Michihiko Aramaki, Kazuhiro Ishii, Shin Minkyung, Sachio Takashima, Masahiro Nakayama, Masayuki Itoh, Barbara Antalffy, Dawna D. Armstrong, Kiyofumi Yamada, Ken Inoue, and Kazunori Nakajima
  • Organizer: Cell Symposia: Big Questions in Neuroscience
  • Place of Presentation: Paradise Point Resort & Spa,San Diego, California, U.S.A.
  • Year and Date: 2016-11-10
  • Int'l Joint Research
• [Presentation] 環境要因としての虚血ストレスが大脳皮質の発達に与える影響 (2016)
  • Author(s): 久保健一郎、出口貴美子、井澤栄一、井上健、仲嶋一範
  • Organizer: フォーラム2016：衛生薬学・環境トキシコロジー
  • Place of Presentation: 昭和大学旗の台キャンパス、品川区(東京都）
  • Year and Date: 2016-09-10
  • Invited
• [Presentation] 神経発達の生物学的な理解を進める必要性について (2016)
  • Author(s): 久保健一郎
  • Organizer: 第38回日本生物学的精神医学会・第59回日本神経化学会大会
  • Place of Presentation: 福岡国際会議場、福岡(福岡県)
  • Year and Date: 2016-09-08
  • Invited
• [Presentation] Reelin coupled with myelin may play a role in long term maintenance of myelin (2016)
  • Author(s): Kimiko Deguchi，Takao Honda, Ken-ichiro Kubo, Kazunori Nakajima,and Ken Inoue
  • Organizer: 第58回日本小児神経学会学術集会
  • Place of Presentation: 京王プラザホテル新宿、新宿(東京都）
  • Year and Date: 2016-06-03
• [Presentation] Reelin coupled with myelin may play a role in long-term maintenance of myelin (2016)
  • Author(s): Kimiko Deguchi, Takao Honda, Ken-ichiro Kubo, Kazunori Nakajima, and Ken Inoue
  • Organizer: 21st Biennial Meeting of the International Society for Developmental Neuroscience (ISDN2016)
  • Place of Presentation: Antibes-Juan les Pins, France
  • Year and Date: 2016-05-11
  • Int'l Joint Research
• [Presentation] ApoER2 controls not only neuronal migration but also termination of migration in the developing cerebral cortex (2016)
  • Author(s): 廣田ゆき、久保健一郎、藤野貴広、山本徳男、仲嶋一範
  • Organizer: 第121回日本解剖学会総会・全国学術集会
  • Place of Presentation: ビッグパレットふくしま(福島県郡山市)
  • Year and Date: 2016-03-28
• [Presentation] Analysis of the molecular mechanisms that underlie Reelin-induced neuronal aggregation in the mouse neocortex (2016)
  • Author(s): Seika Inoue, Kanehiro Hayashi, Ken-ichiro Kubo, and Kazunori Nakajima
  • Organizer: 第９回神経発生討論会・難治疾患共同研究拠点共同開催学術集会
  • Place of Presentation: 東京医科歯科大学Ｍ＆Ｄタワー鈴木章夫記念講堂(東京都文京区)
  • Year and Date: 2016-03-18
• [Presentation] C-terminal region of Reelin is required for development and maintenance of the postnatal cerebral cortex and its functions are regulated by specific proteolysis (2016)
  • Author(s): Takao Kohno, Takao Honda, Ken-ichiro Kubo, Yoshimi Nakano, Ayaka Tsuchiya, Tatsuro Murakami, Hideyuki Banno, Kazunori Nakajima, and Mitsuharu Hattori
  • Organizer: 新学術領域研究「神経細胞の多様性と大脳新皮質の構築」第3回国際シンポジウム「Neocortical Organization 3」
  • Place of Presentation: 東京大学小柴ホール(東京都文京区)
  • Year and Date: 2016-02-11
  • Int'l Joint Research
• [Presentation] ApoER2 controls not only neuronal migration but also termination of migration in the developing cerebral cortex (2016)
  • Author(s): Yuki Hirota, Ken-ichiro Kubo, Takahiro Fujino, Tokuo T. Yamamoto, and Kazunori Nakajima
  • Organizer: 新学術領域研究「神経細胞の多様性と大脳新皮質の構築」第3回国際シンポジウム「Neocortical Organization 3」
  • Place of Presentation: 東京大学小柴ホール(東京都文京区)
  • Year and Date: 2016-02-11
  • Int'l Joint Research
• [Presentation] 子宮内電気穿孔法を用いたマウス脳内神経細胞における活動制御の試み (2016)
  • Author(s): ハズラ デバブラタ、久保健一郎、仲嶋一範
  • Organizer: 日本解剖学会関東支部 第104回学術集会
  • Place of Presentation: 横浜市立大学八景キャンパスYCUスクウェア、横浜(神奈川県）
• [Presentation] Experiment and modeling of the Reelin-dependent modification of intercellular adhesion among cerebral cortical cells (2015)
  • Author(s): Yuki Matsunaga, Mariko Noda, Hideki Murakawa, Takashi Miura, Ken-ichiro Kubo, and Kazunori Nakajima
  • Organizer: 2015 American Society for Cell Biology Annual Meeting
  • Place of Presentation: San Diego Convention Center(San Diego, U.S.A.)
  • Year and Date: 2015-12-12
  • Int'l Joint Research
• [Presentation] 発生期のマウス海馬及び大脳新皮質における特異的な細胞移動様式についての解析 (2015)
  • Author(s): 北澤彩子、シン ミンギョン、林周宏、久保健一郎、仲嶋一範
  • Organizer: 日本解剖学会関東支部 第103回学術集会
  • Place of Presentation: 慶應義塾大学日吉キャンパス(神奈川県横浜市)
  • Year and Date: 2015-11-07
• [Presentation] 異所性灰白質は離れた脳部位の神経活動に影響を与えて行動の異常を引き起こす (2015)
  • Author(s): 久保健一郎、石井一裕、遠藤俊裕、吉田慶太朗、ベナー聖子、伊藤亨子、相澤秀紀、荒巻道彦、山中章弘、田中光一、高田則雄、田中謙二、三村將、遠山千春、掛山正心、仲嶋一範
  • Organizer: 日本解剖学会関東支部 第103回学術集会
  • Place of Presentation: 慶應義塾大学日吉キャンパス(神奈川県横浜市)
  • Year and Date: 2015-11-07
• [Presentation] 大脳皮質神経細胞接着の制御とその数理モデル (2015)
  • Author(s): 松永友貴、野田万理子、村川秀樹、三浦岳、久保健一郎、仲嶋一範
  • Organizer: 日本解剖学会関東支部 第103回学術集会
  • Place of Presentation: 慶應義塾大学日吉キャンパス(神奈川県横浜市)
  • Year and Date: 2015-11-07
• [Presentation] 異所性皮質の作成による大脳皮質組織構築変化の病態理解 (2015)
  • Author(s): 久保健一郎、石井一裕、遠藤俊裕、吉田慶太朗、ベナー聖子、伊藤亨子、相澤秀紀、荒巻道彦、山中章弘、田中光一、高田則雄、田中謙二、三村將、遠山千春、掛山正心、仲嶋一範
  • Organizer: 第50回慶應ニューロサイエンス研究会「システムとしての脳の理解と介入」
  • Place of Presentation: 慶應義塾大学信濃町キャンパス(東京都新宿区)
  • Year and Date: 2015-10-31
• [Presentation] Neuronal heterotopias affect the activities of distant brain areas and lead to behavioral deficits (2015)
  • Author(s): Kazuhiro Ishii, Ken-ichiro Kubo, Toshihiro Endo, Keitaro Yoshida, Seico Benner, Yukiko Ito, Hidenori Aizawa, Michihiko Aramaki, Akihiro Yamanaka, Kohichi Tanaka, Norio Takata, Kenji F. Tanaka, Masaru Mimura, Chiharu Tohyama, Masaki Kakeyama, and Kazunori Nakajima.
  • Organizer: Society for Neuroscience, Neuroscience 2015 meeting
  • Place of Presentation: McCormick Place(Chicago, U.S.A.)
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] Importance of Reelin C-terminal region in the development and maintenance of the postnatal cerebral cortex and its regulation by specific proteolysis (2015)
  • Author(s): Takao Kohno, Takao Honda, Ken-ichiro Kubo, Yoshimi Nakano, Ayaka Tsuchiya, Tatsuro Murakami, Hideyuki Banno, Kazunori Nakajima, and Mitsuharu Hattori.
  • Organizer: Society for Neuroscience, Neuroscience 2015 meeting
  • Place of Presentation: McCormick Place(Chicago, U.S.A.)
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] Application of the in utero electroporation technique to the study of the pathological mechanism of focal heterotopias in the brain (2015)
  • Author(s): Ken-ichiro Kubo, Kazuhiro Ishii, Toshihiro Endo, Keitaro Yoshida, Seico Benner, Yukiko Ito, Hidenori Aizawa, Michihiko Aramaki, Akihiro Yamanaka, Kohichi Tanaka, Norio Takata, Kenji F. Tanaka, Masaru Mimura, Chiharu Tohyama, Masaki Kakeyama, and Kazunori Nakajima
  • Organizer: Cell Symposia: Engineering the Brain – Technologies for Neurobiological Applications
  • Place of Presentation: Drake Hotel(Chicago, U.S.A.)
  • Year and Date: 2015-10-15
  • Int'l Joint Research
• [Presentation] Analyses of the pathological roles of the altered brain cytoarchitectures with ectopic neurons (2015)
  • Author(s): Ken-ichiro Kubo, Kazuhiro Ishii, Toshihiro Endo, Keitaro Yoshida, Seico Benner, Yukiko Ito, Hidenori Aizawa, Michihiko Aramaki, Akihiro Yamanaka, Kohichi Tanaka, Norio Takata, Kenji F. Tanaka, Masaru Mimura, Chiharu Tohyama, Masaki Kakeyama, and Kazunori Nakajima
  • Organizer: 第58回日本神経化学会大会
  • Place of Presentation: 大宮ソニックシティ(埼玉県大宮市)
  • Year and Date: 2015-09-11
• [Presentation] Modeling and analysis and of intercellular adhesion between cells from the developing cerebral cortex (2015)
  • Author(s): Yuki Matsunaga, Mariko Noda, Hideki Murakawa, Takashi Miura, Ken-ichiro Kubo, and Kazunori Nakajima
  • Organizer: 第58回日本神経化学会大会
  • Place of Presentation: 大宮ソニックシティ(埼玉県大宮市)
  • Year and Date: 2015-09-11
• [Presentation] 巨大分泌蛋白質リーリンのC末端領域を介した大脳皮質形成機構 (2015)
  • Author(s): 河野孝夫、本田岳夫、久保健一郎、中野良美、土屋綾香、村上達郎、阪野英幸、仲嶋一範、服部光治
  • Organizer: 第61回日本薬学会東海支部総会・大会
  • Place of Presentation: 名古屋市立大学(愛知県名古屋市)
  • Year and Date: 2015-07-04
• [Presentation] Evidence of a link between TDP-43 and dipeptide repeat protein in c9FTD/ALS (2015)
  • Author(s): Mai Yamakawa, Daisuke Ito, Takao Honda, Ken-ichiro Kubo, Mariko Noda, and Kazunori Nakajima, and Norihiro Suzuki
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 朱鷺メッセ(新潟県新潟市)
  • Year and Date: 2015-05-20