Study on the neurodevelopmental abnormalities induced by the innate immune activation during perinatal period

• Project/Area Number: 25460093
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pharmacology in pharmacy
• Research Institution: Nagoya University
• Principal Investigator: NAGAI Taku 名古屋大学, 医学部附属病院, 准教授 (10377426)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 神経発達 / アストロサイト / 免疫 / 神経発達障害

Outline of Final Research Achievements

Polyriboinosinic-polyribocytidilic acid (polyI:C) is known to induce strong innate immune responses that mimic immune activation by viral infections. Our previous findings suggest that the induction of interferon-induced transmembrane 3 (Ifitm3) in astrocytes has a crucial role in polyI:C-induced neurodevelopmental abnormalities including impairments of dendrite elongation and spine formation, which lead to behavioral impairments in adulthood. Through a quantitative proteomic screen, we identified the candidate proteins of astroglial factors, matrix metalloproteinase-3 (Mmp3) and follistatin like-1 (Fstl1), and Mmp3 function on neuronal development was reported previously. In this study, we characterized the effect of Fstl1 on neuronal development and relationship of Ifitm3 expression. Our results suggest that astroglial Fstl1 is one of possible mediators for neurodevelopmental impairment and the extracellular levels of Fstl1 may be regulated under the control of Ifitm3.

Research Products

• [Journal Article] Phosphoproteomics of the Dopamine Pathway Enables Discovery of Rap1 Activation as a Reward Signal In Vivo (2016)
  • Author(s): Nagai T, Nakamuta S, Kuroda K, Nakauchi S, Nishioka T, Takano T, Zhang X, Tsuboi D, Funahashi Y, Nakano T, Yoshimoto J, Kobayashi K, Uchigashima M, Watanabe M, Miura M, Nishi A, Kobayashi K, Yamada K, Amano M, Kaibuchi K
  • Journal Title: Neuron Volume: 89 (3) Issue: 3 Pages: 550-65
  • DOI: 10.1016/j.neuron.2015.12.019
  • Peer Reviewed / Open Access
• [Journal Article] Prenatal Nicotine Exposure Impairs the Proliferation of Neuronal Progenitors, Leading to Fewer Glutamatergic Neurons in the Medial Prefrontal Cortex. (2016)
  • Author(s): Aoyama Y, Toriumi K, Mouri A, Hattori T, Ueda E, Shimato A, Sakakibara N, Soh Y, Mamiya T, Nagai T, Kim HC, Hiramatsu M, Nabeshima T, Yamada K.
  • Journal Title: Neuropsychopharmacology Volume: 41(2) Issue: 2 Pages: 578-89
  • DOI: 10.1038/npp.2015.186
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Heterozygous Disruption of Autism susceptibility candidate 2 Causes Impaired Emotional Control and Cognitive Memory. (2015)
  • Author(s): Hori K, Nagai T, Shan W, Sakamoto A, Abe M, Yamazaki M, Sakimura K, Yamada K, Hoshino M.
  • Journal Title: PLoS One Volume: 30 Issue: 12 Pages: e0145979-e0145979
  • DOI: 10.1371/journal.pone.0145979
  • Peer Reviewed / Open Access
• [Journal Article] Noradrenergic refinement of glutamatergic neuronal circuits in the lateral superior olivary nucleus before hearing onset. (2015)
  • Author(s): Hirao K, Eto K, Nakahata Y, Ishibashi H, Nagai T, Nabekura J.
  • Journal Title: J Neurophysiol. Volume: 114(3) Issue: 3 Pages: 1974-1986
  • DOI: 10.1152/jn.00813.2014
  • Peer Reviewed / Open Access
• [Journal Article] Stress increases DNA methylation of the neuronal PAS domain 4 (Npas4) gene. (2015)
  • Author(s): Furukawa-Hibi Y, Nagai T, Yun J, Yamada K.
  • Journal Title: Neuroreport. Volume: 26 Issue: 14 Pages: 827-32
  • DOI: 10.1097/wnr.0000000000000430
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Insular neural system controls decision-making in healthy and methamphetamine-treated rats (2015)
  • Author(s): Mizoguchi H, Katahira K, Inutsuka A, Fukumoto K, Nakamura A, Wang T, Nagai T, Sato J, Sawada M, Ohira H,Yamanaka A, Yamada K
  • Journal Title: Proc Natl Acad Sci U S A Volume: 112 (29) Issue: 29 Pages: 3930-3939
  • DOI: 10.1073/pnas.1418014112
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nobiletin, a citrus flavonoid, improves cognitive impairment and reduces soluble Aβ levels in a triple transgenic mouse model of Alzheimer's disease (3XTg-AD). (2015)
  • Author(s): Nakajima, A., Aoyama, Y., Shin, E.J. Nam, Y., Kim, H.C. Nagai, T., Yokosuka, A., Mimaki, Y., Yokoi, T., Ohizumi, Y., Yamada, K.
  • Journal Title: Behav. Brain Res. Volume: 289 Pages: 69-77
  • DOI: 10.1016/j.bbr.2015.04.028
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] FUS regulates AMPA receptor function and FTLD/ALS-associated behaviour via GluA1 mRNA stabilization. (2015)
  • Author(s): Udagawa, T., Fujioka, Y., Tanaka, M., Honda, D., Yokoi, S., Riku, Y., Ibi, D., Nagai, T., Yamada, K., Watanabe, H., Katsuno, M., Inada, T., Ohno, K., Sokabe, M., Okado, H., Ishigaki S*., and Sobue, G.
  • Journal Title: Nat Commun Volume: 6 Issue: 1 Pages: 7098-7098
  • DOI: 10.1038/ncomms8098
  • Peer Reviewed / Open Access
• [Journal Article] Reelin has a preventive effect on phencyclidine-induced cognitive and sensory-motor gating deficits (2015)
  • Author(s): Kazuhiro Ishii, Taku Nagai, Yuki Hirota, Mariko Noda, Toshitaka Nabeshima, Kiyofumi Yamada, Ken-ichiro Kubo, and Kazunori Nakajima
  • Journal Title: Neurosci. Res. Volume: 印刷中 Pages: 30-36
  • DOI: 10.1016/j.neures.2014.12.013
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Matrix metalloproteinase-3 is a possible mediator of neurodevelopmental impairment due to polyl : C-induced innate immune activation of astrocytes (2014)
  • Author(s): S Yamada, T Nagai, T Nakai, D Ibi, A Nakajima, K Yamada
  • Journal Title: Brain, Behavior, and Immunity Volume: 38 Pages: 272-282
  • DOI: 10.1016/j.bbi.2014.02.014
  • Peer Reviewed
• [Journal Article] Alterations of GABAergic and dopaminergic system in mutant mice with disruption of exons 2 and 3 of the Disc1 gene. (2014)
  • Author(s): Nakai T, Nagai T, Wang R, Yamada S, Kuroda K, Kaibuchi K, Yamada K
  • Journal Title: Neurochem. Int. Volume: 74 Pages: 74-83
  • DOI: 10.1016/j.neuint.2014.06.009
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Girdin phosphorylation is crucial for synaptic plasticity and memory: A potential role in the interaction of BDNF/TrkB/Akt signaling with NMDA receptor (2014)
  • Author(s): Tsuyoshi Nakai, Taku Nagai, Motoki Tanaka, Norimichi Itoh, Naoya Asai, Atsushi Enomoto, Masato Asai, Shinnnosuke Yamada, Ali Bin Saifullah, Masahiro Sokabe, Masahide Takahashi, Kiyofumi Yamada
  • Journal Title: The Journal of Neuroscience Volume: 34 Issue: 45 Pages: 14995-15008
  • DOI: 10.1523/jneurosci.2228-14.2014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Flexシステムを用いた脳内報酬系の解析：ドパミンD1受容体発現中型有棘細胞の動作メカニズムの解明. (2016)
  • Author(s): 永井拓, 天野睦紀, 山田清文, 貝淵弘三.
  • Organizer: 第89回日本薬理学会年会.
  • Place of Presentation: 神奈川県横浜市パシフィコ横浜
  • Year and Date: 2016-03-09
• [Presentation] 報酬関連行動を制御するシグナル伝達 (2015)
  • Author(s): 永井拓
  • Organizer: 蛋白研セミナー・包括脳ネットワーク研究会 「第6回神経科学と構造生物学の融合研究会」
  • Place of Presentation: 愛知県岡崎市生理学研究所
  • Year and Date: 2015-11-26
  • Invited
• [Presentation] 薬物依存症の克服を目指した分子基盤研究 (2015)
  • Author(s): 永井拓
  • Organizer: 平成27年度アルコール・薬物依存関連学会合同学術総会
  • Place of Presentation: 兵庫県神戸市神戸国際会議場
  • Year and Date: 2015-10-11
  • Invited
• [Presentation] 報酬シグナルの同定と報酬回路の制御機構 (2015)
  • Author(s): 永井拓
  • Organizer: 平成27年度アルコール・薬物依存関連学会合同学術総会
  • Place of Presentation: 兵庫県神戸市神戸国際会議場
  • Year and Date: 2015-10-11
• [Presentation] ドパミン神経伝達を介した報酬シグナルの多面的解析 (2015)
  • Author(s): 269.永井拓
  • Organizer: 平成27年度生理学研究所研究会「情動の多次元的理解に基づく行動原理の探求」
  • Place of Presentation: 愛知県岡崎市生理学研究所
  • Year and Date: 2015-10-07
  • Invited
• [Presentation] リン酸化プロテオミクスによる報酬シグナルの解明 (2015)
  • Author(s): 永井拓, 天野睦紀, 山田清文, 貝淵弘三
  • Organizer: 第58回日本神経化学会大会
  • Place of Presentation: 埼玉県さいたま市大宮ソニックシティ
  • Year and Date: 2015-09-11
• [Presentation] Intracellular signal transduction in the brain reward system (2015)
  • Author(s): 永井拓
  • Organizer: 第88回日本薬理学会年会 (シンポジウム)
  • Place of Presentation: 愛知県名古屋市、名古屋国際会議場
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] リン酸化Girdinによる神経可塑性の制御 (2015)
  • Author(s): 永井拓, 中井剛, 田中基樹, 浅井直也, 榎本篤, 曽我部正博, 高橋雅英, 山田清文.
  • Organizer: 第24回神経行動薬理若手研究者の集い
  • Place of Presentation: 愛知県名古屋市、名城大学名駅サテライトキャンパス
  • Year and Date: 2015-03-17
• [Presentation] リン酸化GirdinはNMDA受容体を介して神経可塑性を制御する (2014)
  • Author(s): 永井拓, 中井剛, 田中基樹, 浅井直也, 榎本篤, 曽我部正博, 高橋雅英, 山田清文.
  • Organizer: 第24回日本臨床精神神経薬理学会・第44回日本神経精神薬理学会 合同年会
  • Place of Presentation: 愛知県名古屋市、名古屋国際会議場
  • Year and Date: 2014-11-20 – 2014-11-22
• [Presentation] Matrix metalloproteinase-3 mediates neurodevelopmental impairment due to polyI:C-induced innate immune activation. (2014)
  • Author(s): 永井拓, 山田真之亮, 山田清文.
  • Organizer: 第8回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 熊本県、熊本市、熊本大学薬学部多目的ホール
  • Year and Date: 2014-11-15 – 2014-11-16
• [Presentation] 脳内報酬系の分子基盤 (2014)
  • Author(s): 永井拓
  • Organizer: 第49回日本アルコール・薬物医学会、第36回日本アルコール関連問題学会、第26回日本依存神経精神科学会合同学術総会.
  • Place of Presentation: 神奈川県横浜市、パシフィコ横浜
  • Year and Date: 2014-10-03 – 2014-10-04
• [Presentation] Matrix metalloproteinase-3とpolyI:C誘発性自然免疫活性化により惹起される神経発達障害. (2014)
  • Author(s): 永井拓, 山田真之亮, 山田清文.
  • Organizer: 第37回日本神経科学大会 (Neuroscience2014)
  • Place of Presentation: 神奈川県横浜市、パシフィコ横浜
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] PolyI:C誘発性神経発達障害モデルの有用性 (シンポジウム: 統合失調症失調症の生物学的研究の進歩－遺伝子特性～創薬の種の最前線－) (2013)
  • Author(s): 永井拓
  • Organizer: 第8回日本統合失調症学会
  • Place of Presentation: 北海道浦河郡、浦河町総合文化会館, 浦河ウエリントン ホテル
• [Presentation] 精神発達に及ぼす遺伝―環境因子の影響に関する研究
  • Author(s): 永井拓
  • Organizer: 第59回日本薬学会東海支部総会・大会
  • Place of Presentation: 愛知県名古屋市、名城大学
  • Invited
• [Presentation] 新生仔期polyI:C処置マウスの異常行動に対する抗精神病薬の効果とプロテオーム解析
  • Author(s): 永井拓,千崎康司, Yu Jinghua, 山田清文
  • Organizer: 第123回日本薬理学会近畿部会
  • Place of Presentation: 愛知県名古屋市、ウインクあいち
• [Remarks] 名古屋大学大学院医学系研究科医療薬学・医学部附属病院薬剤部HP
  • URL: http://www.med.nagoya-u.ac.jp/pharmacy/02/outline.html
• [Remarks] 名古屋大学大学院医学系研究科医療薬学・医学部附属病院薬剤部HP
  • URL: http://www.med.nagoya-u.ac.jp/pharmacy/02/outline.html