Mediation of neuronal maturation and spinogenesis by PACAP signaling in primary hippocampal neurons

• Project/Area Number: 25460100
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pharmacology in pharmacy
• Research Institution: Osaka University
• Principal Investigator: HAYATA ATSUKO 大阪大学, 連合小児発達学研究科, 助教 (70390812)
• Co-Investigator(Renkei-kenkyūsha): HASHIMOTO Hitoshi 大阪大学, 大学院薬学研究科, 教授 (30240849)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: PACAP / シナプス病態 / 精神疾患 / 樹状突起スパイン / 初代培養神経細胞 / セロトニン受容体 / 細胞内移行 / 神経細胞 / スパイン / 細胞内局在化

Outline of Final Research Achievements

Recent evidence implicates that abnormalities in dendritic spines are key substrates in the pathogenesis of several neuropsychiatric disorders. In this study, we analyzed the molecular mechanism for the spine maturation and spinogenesis by PACAP signaling. Here, we observed that miR-132 sponge and the MEK1/2 inhibitor U0126 blocked the PACAP-mediated increase in spine maturation and spinogenesis. In contrast, overexpression of miR-132 partly rescued the spine reductions in the PACAP-deficient primary neurons.
These data indicate that PACAP-miRNA132 signaling pathway is critically implicated in spine formation and contribute to understand the molecular mechanisms underlying neuropsychiatric disorders such as schizophrenia.

Research Products

• [Int'l Joint Research] カリフォルニア大学ロサンゼルス校(アメリカ)
• [Journal Article] Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder (2016)
  • Author(s): Hashimoto R, Nakazawa T, Tsurusaki Y, Yasuda Y, Nagayasu K, Matsumura K, Kawashima H, Yamamori H, Fujimoto M, Ohi K, Umeda-Yano S, Fukunaga M, Fujino H, Kasai A, Hayata-Takano A, Shintani N, Takeda M, Matsumoto N, Hashimoto H.
  • Journal Title: J. Hum. Genet. Volume: 61 Pages: 199-206
  • DOI: 10.1038/jhg.2015.141
  • NAID: 40020766278
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Atomoxetine reverses locomotor hyperactivity, impaired novel object recognition, and prepulse inhibition impairment in mice lacking pituitary adenylate cyclase-activating polypeptide (2015)
  • Author(s): hibasaki Y, Hayata-Takano A, Hazama K, Nakazawa T, Shintani N, Kasai A, Nagayasu K, Hashimoto R, Tanida M, Katayama T, Matsuzaki S, Yamada K, Taniike M, Onaka Y, Ago Y, Waschek JA, Köves K, Reglődi D, Tamas A, Matsuda T, Baba A, Hashimoto H.
  • Journal Title: Psychopharmacology (Berl). Volume: 297 Pages: 95-104
  • DOI: 10.1016/j.neuroscience.2015.03.062
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] p13 overexpression in pancreaticβ-cells ameliorates type 2 diabetes in high-fat-fed mice (2015)
  • Author(s): Higashi, S. et al.
  • Journal Title: Biochem Biophys Res Commun. Volume: 461 Pages: 612-617
  • DOI: 10.1016/j.bbrc.2015.04.074
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Comparative gene expression profiles in pancreatic islets associated with agouti yellow mutation and PACAP overexpression in mice (2015)
  • Author(s): Ikeda K, Tomimoto S, Tsuchiya S, Hamagami K, Shintani N, Sugimoto Y, Ichikawa A, Kasai A, Nakazawa T, Nagayasu K, Hayata-Takano A, Baba A, Hashimoto H
  • Journal Title: Biochemistry and Biophysics Reports Volume: 2 Pages: 179-183
  • DOI: 10.1016/j.bbrep.2015.06.006
  • Peer Reviewed / Open Access
• [Journal Article] PACAPシグナルによる精神神経機能調節におけるセロトニン2A受容体シグナルの関与 (2015)
  • Author(s): Hayata A, Hazama K, Moriguchi K, Ago Y, Encho N, Nakazawa T, Nagayasu K, Kasai A, Onaka Y, Shintani N, Baba A, Hashimoto H.
  • Journal Title: 日本神経精神薬理学雑誌 Volume: 35(2) Pages: 55-56
• [Journal Article] PACAP enhances axon and neurite outgrowth in cultured hippocampal neurons to a comparable extent as BDNF. (2015)
  • Author(s): Ogata K, Shintani N, Hayata-takano A, Kamo T, Higashi S, Seiriki K, Momosaki H, Vaudy D, Vaudy H, Galas L, Kasai A, Nagayasu K, Nakazawa T, Hashimoto R, Ago Y, Matsuda T, Baba A, Hashimoto H.
  • Journal Title: PLoS ONE Volume: 10
  • DOI: 10.1371/journal.pone.0120526
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Simultaneous neuron- and astrocyte-specific fluorescent marking. (2015)
  • Author(s): Schulze W, Hayata-Takano A, Kamo T, Nakazawa T, Nagayasu K, Kasai A, Seiriki K, Shintani N, Ago Y, Farfan C, Hashimoto R, Baba A, Hashimoto H.
  • Journal Title: Biochemical and Biophysical Research Communications, Volume: 459 Pages: 81-86
  • DOI: 10.1016/j.bbrc.2015.02.073
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] CRTH2, a prostaglandin D2 receptor, mediates depression-related behavior in mice. (2015)
  • Author(s): Yusuke Onaka, Norihito Shintani, Takanobu Nakazawa, Ryota Haba, Yukio Ago, Hyper Wang, Takuya Kanoh, Atsuko Hayata-Takano, Hiroyuki Hirai, Kin-ya Nagata, Masataka Nakamura, Ryota Hashimoto, Toshio Matsuda, James A. Waschek, Atsushi Kasai, Kazuki Nagayasu, Akemichi Baba, Hitoshi Hashimoto
  • Journal Title: Behav Brain Res Volume: 284 Pages: 131-137
  • DOI: 10.1016/j.bbr.2015.02.013
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Identification of the role of bone morphogenetic protein (BMP) and transforming growth factor-beta (TGF-beta) signaling in the trajectory of serotonergic differentiation in a rapid assay in mouse embryonic stem cells in vitro. (2015)
  • Author(s): Yamasaki A, Kasai A, Toi A, Kurita M, Kimoto S, Hayata-Takano A, Nakazawa T, Nagayasu K, Shintani N, Hashimoto R, Ito A, Meltzer HY, Ago Y, Waschek JA, Onaka Y, matsuda T, Baba A, Hashimoto H.
  • Journal Title: J Neurochem Volume: 132(4) Pages: 418-28
  • DOI: 10.1111/jnc.12999
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Chronic treatment with valproic acid or sodium butyrate attenuates novel object recognition deficits and hippocampal dendritic spine loss in a mouse model of autism. (2014)
  • Author(s): Takuma K, Hara Y, Kataoka S, Kawanai T, Maeda Y, Watanabe R, Takano E, Hayata-Takano A, Hashimoto H, Ago Y, Matsuda T.
  • Journal Title: Pharmacology Biochemistry & Behavior Volume: 126 Pages: 43-49
  • DOI: 10.1016/j.pbb.2014.08.013
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Responses to a Hallucinogenic Drug in PACAP Heterozygous Mutant Mice. (2014)
  • Author(s): Hazama K, Hayata-Takano A, Uetsuki K, Kasai A, Encho N, Shintani N, Nagayasu K, Hashimoto R, Reglodi D, Miyakawa T, Nakazawa T, Baba A, Hashimoto H
  • Journal Title: PLoS One Volume: 9（２）
  • Peer Reviewed
• [Journal Article] The selective metabotropic glutamate 2/3 receptor agonist MGS0028 reverses psychomotor abnormalities and recognition memory deficits in mice lacking the pituitary adenylate cyclase-activating polypeptide. (2013)
  • Author(s): Ago Y
  • Journal Title: Behav. Pharmacol. Volume: 24(1) Pages: 74-77
  • DOI: 10.1097/fbp.0b013e32835cf3e5
  • Peer Reviewed
• [Journal Article] Central PACAP mediates the sympathetic effects of leptin in a tissue-specific manner. (2013)
  • Author(s): 谷田守
  • Journal Title: Neuroscience Volume: 238 Pages: 297-304
  • DOI: 10.1016/j.neuroscience.2013.02.016
  • Peer Reviewed
• [Presentation] マウス新生仔期VPAC2受容体活性化による感覚情報処理機能の障害 (2016)
  • Author(s): 吾郷 由希夫, Michael Condero, 早田 敦子, 河内 琢也, 橋本 均, James Waschek
  • Organizer: 日本薬学会大36年会
  • Place of Presentation: パシフィコ横浜（神奈川・横浜市）
  • Year and Date: 2016-03-26
• [Presentation] 成熟雄性マウスの行動表現型ならびにシナプス関連たんぱく質発現に対するVPAC2受容体活性化の影響 (2016)
  • Author(s): 吾郷 由希夫, Michael Condero, 早田 敦子, 河内 琢也, 橋本 均, James Waschek
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜（神奈川・横浜市）
  • Year and Date: 2016-03-09
• [Presentation] セロトニン神経機能に関わる遺伝子発現に対するmiRNAの作用 (2015)
  • Author(s): 大住 康晃, 永安 一樹, 笠井 淳司, 木本 早紀, 尾中 勇祐, 早田 敦子, 中澤 敬信,新谷 紀人, 橋本 均
  • Organizer: 第128回日本薬理学会近畿部会
  • Place of Presentation: 千里ライフサイエンスセンター（大阪・豊中市）
  • Year and Date: 2015-11-20
• [Presentation] Practical optimization of in situ hybridization procedure for the detection of microRNAs and mRNA expression in brain tissues (2015)
  • Author(s): Kasai A, Kakihara S, Okada R, Hazama K, Nakazawa T, Nagayasu K, Hayata-Takano A, Shintani N, Hashimoto H.
  • Organizer: Neuroscience 2015
  • Place of Presentation: シカゴ（アメリカ）
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] miRNAを介したPACAPによる樹状突起スパイン形成機構 (2015)
  • Author(s): 加茂 俊彦, 早田 敦子, 勢力 薫, 尾形 勝弥, 中澤 敬信, 永安 一樹, 笠井 淳司, 新谷 紀人, 橋本 均
  • Organizer: 第45回日本神経精神薬理学会・第37回日本生物学的精神医学会合同年会
  • Place of Presentation: タワーホール船堀（東京・江戸川区）
  • Year and Date: 2015-09-24
• [Presentation] Overactivation of the VPAC2 receptor during postnatal brain maturation induces changes in synaptic proteins and selective alterations in prepulse inhibition in mice (2015)
  • Author(s): Ago Y, Hayata A, Kawanai T, Hashimoto H, Waschek J.
  • Organizer: 12th International Symposium on VIP/PACAP and Related Peptide
  • Place of Presentation: カッパドキア（トルコ）
  • Year and Date: 2015-09-21
  • Int'l Joint Research
• [Presentation] Roles of PACAP in depression-like behavior (2015)
  • Author(s): Hashimoto H, Shintani N, Ago Y, Hayata-Takano A, Waschek J, Baba A.
  • Organizer: 12th International Symposium on VIP/PACAP and Related Peptide
  • Place of Presentation: カッパドキア（トルコ）
  • Year and Date: 2015-09-21
  • Int'l Joint Research
• [Presentation] Overactivation of the VPAC2 receptor during postnatal brain maturation induces changes in synaptic proteins and selective alterations in prepulse inhibition in mice (2015)
  • Author(s): 吾郷 由希夫, 早田 敦子, 河内 琢也, 尾中 勇祐, 橋本 均, James Waschek.
  • 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・大宮）
  • Year and Date: 2015-09-11
• [Presentation] 慢性的な社会的敗北ストレスによる内側前頭前皮質におけるPACAP発現低下とエピジェネティクス関連因子の発現変化 (2015)
  • Author(s): 川瀬啓生、笠井淳司、小川純明、狭間啓佑、早田敦子、新谷紀人、馬場明道、橋本均
  • Organizer: 日本薬学会 第135年会
  • Place of Presentation: 神戸学院大学（神戸）
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] 神経ペプチドPACAPによる精神機能調節：創薬への展望 (2014)
  • Author(s): 橋本均、新谷紀人、早田敦子、笠井淳司、永安一樹、中澤敬信
  • Organizer: 第36回日本生物学的精神医学会 第57回日本神経化学会大会 合同年会
  • Place of Presentation: 奈良県文化会館（奈良）
  • Year and Date: 2014-09-29 – 2014-10-01
• [Presentation] A crosstalk between PACAP and serotonin 2A signaling (2014)
  • Author(s): Moriguchi K, Hayata A, Michizoe H, Encho N, Shintani N, Baba A, Hashimoto H
  • Organizer: 20th International Symposium on Regulatory Peptides (REGPEG2014)
  • Place of Presentation: 京都ガーデンパレス（京都）
  • Year and Date: 2014-09-07 – 2014-09-10
• [Presentation] コルチコステロン誘発性うつ病モデルを用いたプロスタノイド受容体DP2を介する情動制御機構の解析 (2014)
  • Author(s): 尾中勇祐、新谷紀人、木野村元彦、平井博之、長田欽也、中村正孝、早田敦子、笠井淳司、永安一樹、中澤敬信、馬場明道、橋本均
  • Organizer: 生体機能と創薬シンポジウム2014
  • Place of Presentation: 近畿大学薬学部 東大阪キャンパス（大阪）
  • Year and Date: 2014-08-28 – 2014-08-29
• [Presentation] 脳内miRNA発現の高感度検出に向けたin situ hybridization法の最適化：炎症により発現変化する脳内miRNAの同定 (2014)
  • Author(s): 柿原素楽, 笠井淳司, 岡田遼, 狭間啓佑, 中澤敬信, 永安一樹, 早田敦子, 新谷紀人, 橋本均
  • Organizer: 生体機能と創薬シンポジウム2014
  • Place of Presentation: 近畿大学薬学部 東大阪キャンパス（大阪）
  • Year and Date: 2014-08-28 – 2014-08-29
• [Presentation] PACAP-PAC1 signaling pathway regulates internalization of serotonin 2A receptor in a PKC and b-arrestin2 dependent manner (2014)
  • Author(s): Hayata A, Moriguchi K, Encho N, Shintani N, Baba A, Hashimoto H
  • Organizer: 29th CINP World Congress of Neuropsychopharmacology
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2014-06-22 – 2014-06-26
• [Presentation] PACAP-PAC1 signaling pathway regulates internalization of serotonin 2A receptor via a PKC and beta-arrestin2 dependent manner (2014)
  • Author(s): Atsuko Hayata, Keita Moriguchi, Naoki Encho, Toshihiko Kamo,t Norihito Shinani, Kazuki Nagayasu, Atsushi Kasai, Akemichi Baba, Hitoshi Hashimoto
  • Organizer: 29th CINP world congress of neuropsychopharmacology
  • Place of Presentation: Vancouver, Canada
• [Presentation] Altered expression of PACAP in the mPFC in depression-like states induced by chronic social defeat stress. (2014)
  • Author(s): Hazama K, Kasai A, Ogawa S, Hayata-Takano A, Shintani N, Baba A, Hashimoto H
  • Organizer: 第87回日本薬理学会年会
  • Place of Presentation: 仙台
• [Presentation] Vulnerability to a hallucinogenic drug in PACAP heterozygous mice is accompanied by altered neural response in the somatosensory cortex. (2013)
  • Author(s): Hazama K, Kasai A, Encho N, Hayata-Takano A, Shintani N, Baba A, Hashimoto H
  • Organizer: Neuroscience2013
  • Place of Presentation: San Diego, USA
• [Presentation] PACAP induces PKC-mediated serotonin 2A receptor internalization. (2013)
  • Author(s): Moriguchi K, Hayata-Takano A, Fujino T, Encho N, Nagayasu K, Kasai A, Shintani N, Baba A, Hashimoto H
  • Organizer: 第124回 日本薬理学会近畿部会
  • Place of Presentation: 京都
• [Presentation] PACAP induces internalization of serotonin 2A receptor in a protein kinase C-dependent manner. (2013)
  • Author(s): Hayata-Takano A, Encho N, Moriguchi K, Fujino T, Shintani N, Kasai Baba A A, Hashimoto H
  • Organizer: AsCNP2013
  • Place of Presentation: Beijing, China
• [Presentation] Analysis of PACAP signaling-mediated receptor internalization using the HaloTag system. (2013)
  • Author(s): Hayata-Takano A, Encho N, Moriguchi K, Fujino T, Shintani N, Kasai Baba A A, Hashimoto H
  • Organizer: The 11th international symposium on VIP ,PACAP and related peptide
  • Place of Presentation: Pecs, Hungary
• [Remarks] 大阪大学大学院 薬学研究科 神経薬理学分野
  • URL: http://molpharm.umin.jp/index.html
• [Remarks] 大阪大学大学院 連合小児発達学研究科 付属 子どものこころの分子統御機構研究センター
  • URL: http://www.med.osaka-u.ac.jp/pub/kokoro/top.htm