ヒストン修飾異常に起因する精神病態のマルチスケール解析による構成的理解

• Project Area: Constructive understanding of multi-scale dynamism of neuropsychiatric disorders
• Project/Area Number: 19H05204
• 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: The University of Tokyo
• Principal Investigator: 狩野 方伸 東京大学, 大学院医学系研究科(医学部), 教授 (40185963)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Discontinued (Fiscal Year 2020)
• Budget Amount: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000); Fiscal Year 2020: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2019: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: 統合失調症 / 自閉スペクトラム症 / 神経回路発達 / シナプス伝達 / エピジェネティクス / ヒストン修飾 / 前頭前野 / マウス

Outline of Research at the Start

神経回路の発達過程の障害によって発症する自閉スペクトラム症や統合失調症等の精神疾患に関連する多くの候補遺伝子が同定されており、それらの遺伝子の発現制御機構としてエピジェネティック因子の役割が注目されている。本研究では、これらのうちで精神疾患との関係が多く報告されているヒストン３リジン４メチル化・脱メチル化に着目し、マウスを用いて、同部位のヒストン修飾がシナプス機能や精神疾患類似行動を含めた行動にどのように影響するかを精査する。これにより、精神疾患の病態基盤を成すと考えられる神経回路の発達と機能の障害に関する理解を推進することを目指す。

Outline of Annual Research Achievements

本研究では、エピジェネティック因子のうちで精神疾患との関係が多く報告されているヒストン３リジン４メチル化・脱メチル化に着目し、マウスを用いて、同部位のヒストン修飾がシナプス機能や精神疾患類似行動を含めた行動にどのように影響するかを精査した。特に、統合失調症のリスク遺伝子の一つであり、ヒストン３リジン４トリメチル化酵素をコードするSetd1a遺伝子に注目した。
令和元年度までに、統合失調症患者でみられる変異と同等の変異をマウスのSetd1a遺伝子に導入し、このヘテロ接合体マウス（Setd1a+/- マウス）の電気生理学的および形態学的解析を行ってきた。令和2年度は、引き続き、内側前頭前野の急性脳スライスにおける電気生理学的解析を行い、2/3層錐体細胞の興奮性シナプス伝達、抑制性シナプス伝達、興奮性・抑制性シナプス応答のバランス、細胞膜の受動的性質の解析を行った。その結果、 興奮性シナプス後電流は減弱していたが、抑制性シナプス後電流および細胞膜の受動的性質には変化がなかった。さらに、内側前頭前野の2/3層錐体細胞の樹状突起スパインの形態学的解析を行い、Setd1a+/- マウスでスパイン密度の減少がみられた。また、マウスの網羅的行動解析を行ったところ、Setd1a+/- マウスは、過活動や社会性の障害など、統合失調症類似の行動異常を示すことが明らかになった。これらの結果から、Setd1a+/-マウスは統合失調症の動物モデルとして有用であると考えられた。
また、令和元年度に引き続き、Setd1a以外のヒストン３リジン４メチル化・脱メチル化酵素の遺伝子で、精神疾患に関連する候補遺伝子の解析を行った。その結果、内側前頭前野の2/3層錐体細胞でノックダウンした場合に、シナプス伝達に異常を生ずる遺伝子を同定した。

Research Progress Status

令和2年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和2年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders. (2020)
  • Author(s): Suzuki Toshimitsu、Suzuki Toshifumi、Raveau Matthieu、Miyake Noriko、Sudo Genki、Tsurusaki Yoshinori、Watanabe Takaki、Sugaya Yuki、.....Kano Masanobu、Shimoji Takeyoshi、Matsumoto Naomichi、Yamakawa Kazuhiro
  • Journal Title: Annals of Clinical and Translational Neurology Volume: 7 Issue: 7 Pages: 1117-1131
  • DOI: 10.1002/acn3.51093
  • Peer Reviewed / Open Access
• [Journal Article] Sparse activity of hippocampal adult-born neurons during REM sleep is necessary for memory consolidation (2020)
  • Author(s): Kumar D, Koyanagi I, Carrier-Ruiz A, Vergara P, Srinivasan S, Sugaya Y, Kasuya M, Yu TS, Vogt K, Muratani M, Ohnishi T, Singh S, Teixeira CM, Cherasse Y, Naoi T, Wang Y, Nondhalee P, Osman BAH, Kaneko N, Sawamoto K, Kernie SG, Sakurai T, McHugh TJ, Kano M, Yanagisawa M, Sakaguchi M
  • Journal Title: Neuron Volume: 107 Issue: 3 Pages: 1-14
  • DOI: 10.1016/j.neuron.2020.05.008
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Setd1a Insufficiency in Mice Attenuates Excitatory Synaptic Function and Recapitulates Schizophrenia-Related Behavioral Abnormalities (2020)
  • Author(s): Nagahama Kenichiro、Sakoori Kazuto、Watanabe Takaki、Kishi Yusuke、Kawaji Keita、Koebis Michinori、Nakao Kazuki、Gotoh Yukiko、Aiba Atsu、Uesaka Naofumi、Kano Masanobu
  • Journal Title: Cell Reports Volume: 32 Issue: 11 Pages: 108126-108126
  • DOI: 10.1016/j.celrep.2020.108126
  • Peer Reviewed / Open Access
• [Journal Article] Autism spectrum disorder-like behavior caused by reduced excitatory synaptic transmission in pyramidal neurons of mouse prefrontal cortex. (2020)
  • Author(s): Sacai Hiroaki、Sakoori Kazuto、Konno Kohtarou、Nagahama Kenichiro、Suzuki Honoka、Watanabe Takaki、Watanabe Masahiko、Uesaka Naofumi、Kano Masanobu
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 5140-5140
  • DOI: 10.1038/s41467-020-18861-3
  • Peer Reviewed / Open Access
• [Journal Article] G Protein-Coupled Glutamate and GABA Receptors Form Complexes and Mutually Modulate Their Signals (2020)
  • Author(s): Sakairi Hakushun、Kamikubo Yuji、Abe Masayoshi、Ikeda Keisuke、Ichiki Arata、Tabata Toshihide、Kano Masanobu、Sakurai Takashi
  • Journal Title: ACS Chemical Neuroscience Volume: 11 Issue: 4 Pages: 567-578
  • DOI: 10.1021/acschemneuro.9b00599
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive analysis of a novel mouse model of the 22q11.2 deletion syndrome: a model with the most common 3.0-Mb deletion at the human 22q11.2 locus (2020)
  • Author(s): Saito Ryo、Koebis Michinori、Nagai Taku、Shimizu Kimiko、Liao Jingzhu、Wulaer Bolati、Sugaya Yuki、Nagahama Kenichiro、Uesaka Naofumi、Kushima Itaru、Mori Daisuke、Maruyama Kazuaki、Nakao Kazuki、Kurihara Hiroki、Yamada Kiyofumi、Kano Masanobu、Fukada Yoshitaka、Ozaki Norio、Aiba Atsu
  • Journal Title: Translational Psychiatry Volume: 10 Issue: 1 Pages: 35-35
  • DOI: 10.1038/s41398-020-0723-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Glial-Neuronal Circuit in the Median Eminence Regulates Thyrotropin-Releasing Hormone-Release via the Endocannabinoid System (2020)
  • Author(s): Farkas Erzsevet、Varga Edina、Kovacs Balazs、....、Watanabe Masahiko、Kano Masanobu、...、Charli Jean-Louis、Joseph-Bravo Patricia、Fekete Csaba
  • Journal Title: iScience Volume: 23 Issue: 3 Pages: 100921-100921
  • DOI: 10.1016/j.isci.2020.100921
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
• [Journal Article] mGluR1 in cerebellar Purkinje cells is essential for the formation but not expression of associative eyeblink memory (2019)
  • Author(s): Nakao Harumi、Kishimoto Yasushi、Hashimoto Kouichi、Kitamura Kazuo、Yamasaki Miwako、Nakao Kazuki、Watanabe Masahiko、Kano Masanobu、Kirino Yutaka、Aiba Atsu
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 7353-7353
  • DOI: 10.1038/s41598-019-43744-z
  • Peer Reviewed / Open Access
• [Journal Article] Developmental synapse remodeling in the cerebellum and visual thalamus. (2019)
  • Author(s): Kano M, Watanabe T.
  • Journal Title: F1000Research Volume: 8 Pages: 1191-1191
  • DOI: 10.12688/f1000research.18903.1
  • Peer Reviewed / Open Access
• [Journal Article] Monoacylglycerol lipase blockade impairs fine motor coordination and triggers cerebellar neuroinflammation through cyclooxygenase-2 (2019)
  • Author(s): Martinez-Torres Sara、Cutando Laura、Pastor Antoni、Kato Ako、Sakimura Kenji、de la Torre Rafael、Valjent Emmanuel、Maldonado Rafael、Kano Masanobu、Ozaita Andres
  • Journal Title: Brain, Behavior, and Immunity Volume: 81 Pages: 399-409
  • DOI: 10.1016/j.bbi.2019.06.036
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Modular organization of cerebellar climbing fiber inputs during goal-directed behavior. (2019)
  • Author(s): Tsutsumi S, Hidaka N, Isomura Y, Matsuzaki M, Sakimura K, Kano M, Kitamura K.
  • Journal Title: Elife. Volume: 8
  • DOI: 10.7554/elife.47021
  • Peer Reviewed / Open Access
• [Journal Article] Endocannabinoid signaling from 2-arachidonoylglycerol to CB1 cannabinoid receptor facilitates reward-based learning of motor sequence. (2019)
  • Author(s): Tanigami H, Yoneda M, Tabata Y, Echigo R, Kikuchi Y, Yamazaki M, Kishimoto Y, Sakimura K, Kano M, Ohno-Shosaku T
  • Journal Title: Neuroscience Volume: 421 Pages: 1-16
  • DOI: 10.1016/j.neuroscience.2019.09.040
  • Peer Reviewed
• [Presentation] Shaping mature neural circuits through synapse pruning (2020)
  • Author(s): Masanobu Kano
  • Organizer: 第43回日本神経科学大会
  • Int'l Joint Research / Invited
• [Presentation] The transcription factor ZFP64 facilitates climbing-fiber synapse elimination along signaling pathway mediated by P/Q-type voltage-dependent Ca2+ channel in the developing cerebellum (2020)
  • Author(s): Jianling Zhang, Takaki Watanabe, Naofumi Uesaka, Masanobu Kano
  • Organizer: 第43回日本神経科学大会
  • Int'l Joint Research
• [Presentation] Protocadherin 10 delays developmental climbing fiber synapse elimination in a subset of aldolase C-positive Purkinje cells in the cerebellum (2020)
  • Author(s): Takaki Watanabe, Kazuto Sakoori, Honoka Suzuki, Tsubasa Akamatsu, Kyoko Matsuyama, Shutaro Inoue, Manabu Abe, Kenji Sakimura, Naofumi Uesaka, Masanobu Kano
  • Organizer: 第43回日本神経科学大会
  • Int'l Joint Research
• [Presentation] Visualizing Network Level Endocannabinoid Signaling in the Hippocampus (2020)
  • Author(s): Henry Paul Denny, Ao Dong, Kaikai He, Yulong Li, Yuki Sugaya, Masanobu Kano
  • Organizer: 第43回日本神経科学大会
  • Int'l Joint Research
• [Presentation] Protocadherin 10 delays developmental climbing fiber synapse elimination in a subset of aldolase C-positive Purkinje cells in the cerebellum (2020)
  • Author(s): Takaki Watanabe, Honoka Suzuki, Kazuto Sakoori, Shutaro Inoue, Tsubasa Akamatsu, Manabu Abe, Kenji Sakimura, Naofumi Uesaka, Masanobu Kano
  • Organizer: 第97回日本生理学会
  • Int'l Joint Research
• [Presentation] The endocannabinoid 2-arachidonoyl glycerol in dentate granule cells suppresses kainate-induced seizures (2020)
  • Author(s): Yuki Sugaya, Kenji Sakimura, Masanobu Kano
  • Organizer: 第97回日本生理学会
  • Int'l Joint Research
• [Presentation] Cerebellar climbing fiber signals represent voluntary forelimb lever-pull trajectories (2019)
  • Author(s): Naoki Hidaka, Koji Ikezoe, Shinichiro Tsutsumi, Yoshikazu Isomura, Masanobu Kano, Kazuo Kitamura
  • Organizer: 第42回日本神経科学大会
  • Int'l Joint Research
• [Presentation] Loss of the psychiatric disorder-related epigenetic factor reduces excitatory synaptic inputs to pyramidal neurons of the medial prefrontal cortex and causes abnormal behavior in mice (2019)
  • Author(s): Kenichiro Nagahama, Kazuto Sakoori Takaki Watanabe, Michinori Koebis, Naofumi Uesaka, Atsu Aiba, Masanobu Kano
  • Organizer: 第42回日本神経科学大会
  • Int'l Joint Research
• [Presentation] Rational engineering of XCaMPs, a multiclolor GECI suite for in vivo imaging of complex brain circuit dynamics (2019)
  • Author(s): Masatoshi Inoue, Atsuya Takeuchi, Satoshi Manita, ..., Masanobu Kano, Hajime Fujii Deisseroth Karl, Kazuo Kitamura, Haruhiko Bito
  • Organizer: 第42回日本神経科学大会
  • Int'l Joint Research
• [Presentation] AiCE mouse: A novel tool to probe LTP-related change in dendritic spines (2019)
  • Author(s): Kazuya Kuboyama, Takafumi Inoue, Yuki Hashimotodani, Takuya Itoh, Tohsuke Suzuki, Yosuke Ohtuska, Ryo Kinoshita, Pooja Gusain, Masanobu Kano, Shigeo Okabe, Maki K Yamada
  • Organizer: 第42回日本神経科学大会
  • Int'l Joint Research
• [Presentation] Assessment of visual evoked potential in a mouse line with 22q11.2 deletion, a putative mouse model of schizophrenia (2019)
  • Author(s): Ryo Saito, Michinori Koebis, Yuki Sugaya, Masanobu Kano, Atsu Aiba
  • Organizer: 第42回日本神経科学大会
  • Int'l Joint Research
• [Presentation] Climbing fiber synapse elimination in aldolase C-positive Purkinje cells is delayed compared to aldolase C-positive Purkinje cells and requires phospholipase C β3 in the developmental cerebellum (2019)
  • Author(s): Takaki Watanabe, Yurie Rai, Honoka Suzuki, Tsubasa Akamatsu, Naofumi Uesaka, Masanobu Kano
  • Organizer: 第42回日本神経科学大会
  • Int'l Joint Research
• [Presentation] Modulation of dentate granule cell activity during fear memory extinction in freely moving mice (2019)
  • Author(s): Alvaro Carrier Ruiz, Yuki Sugaya, Masanobu Kano
  • Organizer: 第42回日本神経科学大会
  • Int'l Joint Research
• [Presentation] Neural mechanisms of synapse remodeling in the developing brain (2019)
  • Author(s): Masanobu Kano
  • Organizer: The 10th IBRO World Congress of Neuroscience
  • Int'l Joint Research / Invited
• [Presentation] Function of adult-born neurons in maturation of fear memory engram during sleep (2019)
  • Author(s): Masanori Sakaguchi, Iyo Koyanagi, Alvaro Carrier-Ruiz, Pable Vergara, ... Masanobu Kano, Masashi Yanagisawa, Deependra Kumar
  • Organizer: The 10th IBRO World Congress of Neuroscience
  • Int'l Joint Research
• [Presentation] Expression mapping, quantification, and complex formation of GluD1 and GluD2 glutamate receptors in adult mouse brain (2019)
  • Author(s): Kohtarou Konno, Chihiro Nakamoto, Kenji Sakimura, Masanobu Kano, Masahiko Watanabe
  • Organizer: The 10th IBRO World Congress of Neuroscience
  • Int'l Joint Research
• [Presentation] Synapse remodeling in developing Purkinje cells (2019)
  • Author(s): Kano, Masanobu
  • Organizer: Society for Neuroscience
  • Int'l Joint Research
• [Presentation] Cellular and Circuit Mechanisms of Developmental Synapse Pruning in the Cerebellum (2019)
  • Author(s): Kano, Masanobu
  • Organizer: NUS Neuroscience & Technology Symposium
  • Int'l Joint Research / Invited