Abnormal brain cytokine signaling in neurobehavioral impairments

• Project/Area Number: 18390097
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Niigata University
• Principal Investigator: NAWA Hiroyuki Niigata University, 脳研究所, 教授 (50183083)
• Co-Investigator(Kenkyū-buntansha): NAMBA Hisaaki 新潟大学, 脳研究所, 助教 (90332650)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥16,220,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥2,520,000); Fiscal Year 2008: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2007: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2006: ¥5,300,000 (Direct Cost: ¥5,300,000)
• Keywords: サイトカイン / 統合失調症 / 自閉症 / 上皮成長因子 / ニューレグリン / 脳発達 / プレパルスインヒビション / プロスタグランジン / 認知行動 / EGF / IL-1

Research Abstract

上皮成長因子やニューレグリン1の受容体が胎児のGABA神経細胞や中脳ドーパミン神経に発現していることから、これらの神経細胞への影響を培養系と動物で調べ、認知行動発達障害との関係を研究した.上皮成長因子とニューレグリン1は、共に中脳ドーパミン神経の発達、もしくは神経活動を促進したのに対し、もう一方の標的細胞であるGABA神経細胞では全く逆の生理活性を発揮した.新生仔動物への上皮成長因子やニューレグリン1投与は、当該シグナルを感化させ、in vivoのドーパミン発達をかく乱し、その後の認知行動異常を誘発した.これらのドーパミン神経栄養因子は脳血液関門が完成していない時期、血中から中脳に透過し、ドーパミン発達を障害することが明らかになった.

Research Products

• [Journal Article] Prog Neuropsychopharmacol Biol (2009)
  • Author(s): Zheng Y, Watakabe A, Takada M, Kakita A, Namba H, Takahashi H, Yamamori T, Nawa H.
  • Journal Title: Psychiatry 15 ; 33(4) Pages: 701-706
• [Journal Article] In situ hybridization reveals developmental regulation of ErbB1-4 mRNA expression in mouse midbrain : implication of ErbB receptors for dopaminergic neurons (2009)
  • Author(s): Abe Y, Namba H, Zheng Y, Nawa H
  • Journal Title: Neuroscience (in press)
• [Journal Article] Epidermal growth factor administered in the periphery influences excitatory synaptic inputs onto midbrain dopaminergic neurons in postnatal mice (2009)
  • Author(s): Namba H, Zheng Y, Abe Y, Nawa H
  • Journal Title: Neuroscience 18 ; 158(4) Pages: 1731-1741
• [Journal Article] Expression of ErbB4 in substantia nigra dopamineneurons of monkeys and humans. (2009)
  • Author(s): Zheng Y, 他7名
  • Journal Title: Prog Neuropsychopharmacol Biol Psychiatry (印刷中)
  • Peer Reviewed
• [Journal Article] In situ hybridization reveals developmental regulation of ErbB1-4 mRNA expression in mouse midbrain: Implication of ErbB receptors for dopaminergic neurons (2009)
  • Author(s): Abe Y, 他3名
  • Journal Title: Neuroscience (印刷中)
  • Peer Reviewed
• [Journal Article] Activation of epidermal growth factor receptor ErbBl at tenuates inhibitory synaptic development in mouse dentate gyrus. (2009)
  • Author(s): Abe Y, 他2名
  • Journal Title: Neurosci Res 63 Pages: 138-148
  • Peer Reviewed
• [Journal Article] Epidermal Growth factor administered in the periphery influences excitatory synaptic inputs onto midbrain dopaminergic neurons in postnatal mice. (2009)
  • Author(s): Namba H, 他3名
  • Journal Title: Neurosci Res 158 Pages: 1731-1741
  • Peer Reviewed
• [Journal Article] Common behavioral influences of the ErbB1 ligands transforming growth factor alpha and epiregulin administered to mouse neonates (2008)
  • Author(s): Tsuda N, Mizuno M, Yamanaka T, Komurasaki T, Yoshimoto M, Nawa H
  • Journal Title: Brain Dev 30(8) Pages: 533-543
  • NAID: 10025577732
• [Journal Article] The anthraquinone derivative Emodin ameliorates neurobehavioral deficits of a rodent model for schizophrenia (2008)
  • Author(s): Mizuno M, Kawamura H, Takei N, Nawa H
  • Journal Title: J Neural Transm 115(3) Pages: 521-530
• [Journal Article] Common behavioral influences of the ErbB1 ligands transforming growth factor alpha and epiregulin administered to mouse neonates. (2008)
  • Author(s): Tsuda N, 他 5名
  • Journal Title: Brain & Development (印刷中)
  • Peer Reviewed
• [Journal Article] The anthraquinone derivative Emodin ameliorates neurobehavioral deficits of a rodent model for schizophrenia. (2008)
  • Author(s): Mizuno M, 他 3名
  • Journal Title: J Neural Transm. (印刷中)
  • Peer Reviewed
• [Journal Article] The cellular and behavioral consequences of interleukin-1 alpha penetration through the blood-brain barrier of neonatal rats : a critical period for efficacy (2007)
  • Author(s): Tohmi M, Tsuda N, Zheng Y, Mizuno M, Sotoyama H, Shibuya M, Kawamura M, Kakita A, Takahashi H, Nawa H
  • Journal Title: Neuroscience 30 ; 150(1) Pages: 234-250
• [Journal Article] A cyclooxygenase-2 inhibitor ameliorates behavioral impairments induced by striatal administration of epidermal growth factor (2007)
  • Author(s): Mizuno M, Sotoyama H, Narita E, Kawamura H, Namba H, Zheng Y, Eda T, Nawa H
  • Journal Title: J Neurosci 19 ; 27(38) Pages: 10116-10127
• [Journal Article] In vivo administraton of epidermal growth factor and its homologue attenuated developmental maturation of functional excitatory synapses in cortical GABAergic neurons (2007)
  • Author(s): Nagano T, Namba H, Abe Y, Aoki H, Takei N, Nawa H
  • Journal Title: Eur J Neurosci 25 ; (2) Pages: 380-390
• [Journal Article] Neonatal exposure to epidermal growth factor induces dopamine D2-like receptor supersensitivity in adult sensorimotor gating (2007)
  • Author(s): Sotoyama H, Namba H, Takei H, Nawa H
  • Journal Title: Psychopharmacology (Ber1) 191(3) Pages: 783-792
• [Journal Article] A cyclooxygenase-2 inhibitor ameliorates behavioral impairments induced by striatal administration of epidermal growth factor. (2007)
  • Author(s): Mizuno M, 他 7名
  • Journal Title: J Neurosci. 27 Pages: 10116-10127
  • Peer Reviewed
• [Journal Article] The cellular and behavioral consequences of interleukin-1 alpha penetration through the blood-brain barrier of neonatal rats: a critical period for efficacy. (2007)
  • Author(s): Tohmi M, 他 9名
  • Journal Title: Neuroscience. 150 Pages: 234-250
  • Peer Reviewed
• [Journal Article] Activity-dependent shedding of heparin-binding EGF-like growth factor in brain neurons (2006)
  • Author(s): Shishido Y, Tanaka T, Piao YS, Araki K, Takei N, Higashiyama S, Nawa H
  • Journal Title: Biochem Biophys Res Commun 29 ; 348(3) Pages: 963-970
• [Journal Article] Recent progress in animal modeling of immune influammatory processes in schizophrenia : implication of specific cytokines (2006)
  • Author(s): Nawa H, Takei
  • Journal Title: Neurosci Res 56(1) Pages: 2-13
• [Journal Article] Activity-dependent shedding of heparin-binding EGF-like growth factor in brain neurons. (2006)
  • Author(s): Shishido Y, 他6名
  • Journal Title: Biochem Biophys Res Commun. 348(3) Pages: 963-970
• [Journal Article] Recent progress in animal modeling of immune inflammatory processes in schizophrenia : implication of specific cytokines. (2006)
  • Author(s): Nawa H, Takei N.
  • Journal Title: Neurosci Res. 56(1) Pages: 2-13
  • NAID: 10018771439
• [Presentation] Molecular and behavioral analyses of a non-human primate model for schizophrenia (2008)
  • Author(s): Nawa H
  • Organizer: 第31回日本分子生物学会年会/第81回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-12
• [Presentation] Molecular and behavioral analyses of a non-human primate model for schizophrenia (2008)
  • Author(s): Hiroyuki Nawa
  • Organizer: 第31回日本分子生物学会年会/第81回日本生化学会大会合同大会
  • Place of Presentation: 神戸市
  • Year and Date: 2008-12-12
• [Presentation] イボテン酸投与統合失調症モデルラットにおけるチロシン受容体阻害剤の効果 (2008)
  • Author(s): 水野誠、鄭英君、川村宏樹、渋谷雅子、朴英善、外山英和、江田岳誉、那波宏之
  • Organizer: 第51回日本神経化学会大会
  • Place of Presentation: 富山
  • Year and Date: 2008-09-13
• [Presentation] ニューレグリン・EGFシグナル阻害剤が有する抗精神病活性 (2008)
  • Author(s): 那波宏之、加藤泰介、阿部祐一、外山英和、難波寿明、水野誠
  • Organizer: 第51回日本神経化学会大会
  • Place of Presentation: 富山
  • Year and Date: 2008-09-12
• [Presentation] 新生仔期ニューレグリン1-ベータ1暴露は成熟後のMK801感受性を増強する (2008)
  • Author(s): 加藤泰介、水野誠、那波宏之
  • Organizer: 第51回日本神経化学会大会
  • Place of Presentation: 富山
  • Year and Date: 2008-09-12
• [Presentation] 新生期上皮成長因子によるドーパミンD2受容体感受性の亢進と大脳基底核GABA作動性路に対する影響 (2008)
  • Author(s): 外山英和、那波宏之
  • Organizer: 第51回日本神経化学会大会
  • Place of Presentation: 富山
  • Year and Date: 2008-09-12
• [Presentation] 脳発達障害のモデル研究 ; サイトカインの関与 (2008)
  • Author(s): 那波宏之
  • Organizer: 第38回新潟神経学夏季セミナー
  • Place of Presentation: 新潟
  • Year and Date: 2008-08-29
• [Presentation] Epidermal Growth Factor Challenge to A Cynomolgus Monkey Neonate and Its Behavioral Consequences (2008)
  • Author(s): Nawa H
  • Organizer: The 2nd WESBF Asia-Paciifc Congress
  • Place of Presentation: 富山
  • Year and Date: 2008-07-11
• [Presentation] Epidermal Growth Factor Challenge to A Cynomolgus Monkey Neonate and Its Behavioral Consequences. (2008)
  • Author(s): Hiroyuki Nawa
  • Organizer: The 2^<nd> WFSBP Asia-Paciifc Congress
  • Place of Presentation: 富山市
  • Year and Date: 2008-07-11
• [Presentation] ErbB1受容体リガンドは大脳皮質ニューロンの前シナプス発達を阻害する (2008)
  • Author(s): 那波宏之、武井延之、柿田明美、高橋均、横幕大作
  • Organizer: 第31回日本神経科学学会
  • Place of Presentation: 東京
  • Year and Date: 2008-07-10
• [Presentation] ニューレグリンー1・ErbB4慢性刺激による皮質パルアルブミン陽性細胞のグルタミン作動性シナプスに及ぼす影響 (2008)
  • Author(s): 阿部祐一、難波寿明、尾崎美和子、那波宏之
  • Organizer: 第31回日本神経科学学会
  • Place of Presentation: 東京
• [Presentation] Neuregulin-1 enhances glutamatergic synapse maturation of GABAergic interneuron in developing neocortex (2008)
  • Author(s): Abe Y., Namba H, Takei H, Nawa H
  • Organizer: 38th Annual Meeting of Sociey for Neuroscience
  • Place of Presentation: Washington DC
• [Presentation] 統合失調症の網羅的分子病態にみられた脳内炎症以上を分子標的とする創薬への試み (2007)
  • Author(s): 那波宏之
  • Organizer: 第15回日本精神行動遺伝医学会
  • Place of Presentation: 国立精神神経センター, 小平
  • Year and Date: 2007-11-17
• [Presentation] 統合失調症の網羅的分子病態にみられた脳内炎症以上を分子標的とする創薬への試み (2007)
  • Author(s): 那波宏之
  • Organizer: 第15回日本精神行動遺伝医学会
  • Place of Presentation: 国立精神神経センター
  • Year and Date: 2007-11-17
• [Presentation] Effects of emodijn for behavioral impairment in models of schizophrenia (2007)
  • Author(s): Mizuno M, Kawamura H, Nawa H
  • Organizer: 38th Annual Meeting of Society for Neuroscience
  • Place of Presentation: Washington DC
• [Presentation] Neonatal exposure to neuregulin-1 results in distinct behavioral abnormalities in mice ; Comparisn with other cytokine treatments (2007)
  • Author(s): Nawa H, Kato T, Abe Y, Mizuno M, Araki K, Takei N, Ozaki M
  • Organizer: Int Schizophrenia Congress
  • Place of Presentation: Colorado Spring
• [Presentation] Minocycline improves cognitive and behavioral impairments resulted from neonatal exposure to interleukin-1 (2007)
  • Author(s): Tsuda N, Eda T, Mizuno M, Sotoyama H, Nawa H
  • Organizer: The 37th Society for Neuroscience Meeting
  • Place of Presentation: San Diego
• [Presentation] EGF receptor expression of nigral dopamine neurons in human and monkey ; impact on Parkinsonism (2007)
  • Author(s): Zheng Y, Iwakura Y, Takada M, Namba H, Takei N, Kakita A, Takahashi H, Nawa H
  • Organizer: The 37th Society for Neuroscience Meeting
  • Place of Presentation: San Diego
• [Presentation] 統合失調症モデルの認知行動機能障害に対するエモジンの効果 (2007)
  • Author(s): 川村宏樹、水野誠、那波宏之
  • Organizer: 第50回日本神経化学会
  • Place of Presentation: 横浜
• [Presentation] ErbB1遺伝子改変動動物の作製および行動解析 (2007)
  • Author(s): 今野公博、熊谷春乃、荒木一明、糸原重美、那波宏之
  • Organizer: 第50回日本神経化学会
  • Place of Presentation: 横浜
• [Presentation] 幼若期上皮成長因子投与マウスの前頭皮質、海馬におけるGABA抑制機能の低下 (2007)
  • Author(s): 難波寿明、阿部祐一、那波宏之
  • Organizer: 第30回日本神経科学会
  • Place of Presentation: 横浜
• [Presentation] In vivo Action of ErbB ligands on synaptic development and neurobehavioral consequences ; Implication in schizophrenia (2006)
  • Author(s): Nawa H, Kato T, Tsuda N, Mizuno M, Takei N, Ozaki M, Yokomaku D
  • Organizer: APSN
  • Place of Presentation: Singapore
• [Presentation] Postnatal ErbB1 stimulation potentiates excitatory synaptic inputs to midbrain dopaminergic neurons (2006)
  • Author(s): Namba H, Zheng Y, Nawa H
  • Organizer: Soc. Neurosci. Abstr
  • Place of Presentation: Atlanta(341.7)
• [Presentation] Striatal epidermal growth factor signals influences dopamine metabolism and functins (2006)
  • Author(s): Mizuno M, Narita E, Kawamura H, Eda T, Nawa H
  • Organizer: Soc. Neurosci. Abstr
  • Place of Presentation: Atlanta(589.7)
• [Presentation] Neonatal administration of ErbB1 ligands commoly induce postpubertal cognitive behavioral change (2006)
  • Author(s): Tsuda N, Mizuno M, Nawa H
  • Organizer: Soc. Neurosci. Abstr
  • Place of Presentation: Atlanta(687.5)
• [Presentation] Striatal infusion of EGF promotes proliferation of neural stem cells and affects behavioral traits (2006)
  • Author(s): narita E, Mizuno M, Eda T, Kakita A, Nawa H
  • Organizer: The 49th Japan Neurochemistry Socirty Annual Meeting
  • Place of Presentation: 名古屋
• [Presentation] Striatal epidermal growth factor receptor activation on dopamine metabolism and functions (2006)
  • Author(s): Mizuno M, Narita E, Kawamura H, Eda T, Nawa H
  • Organizer: The 49th Japan Neurochemistry Society Annual Meeting
  • Place of Presentation: 名古屋
• [Presentation] Neonatal exposure to EGF receptor ligands commonly produces later behavioral impairments in mice (2006)
  • Author(s): Tsuda N, Mizuno M, Komurasaki T, Yoshimoto M, Nawa H
  • Organizer: The 49th Japan Neurochemistry Society Annual Meeting
  • Place of Presentation: 名古屋