PACAP induces spine morphogenesis and synaptic function via miRNA upregulation.

• Project/Area Number: 16K08269
• 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)
• Research Collaborator: HASHIMOTO Hitoshi 大阪大学, 大学院薬学研究科, 教授 (30240849) ; NAKAZAWA Takanobu 大阪大学, 大学院歯学研究科, 准教授 (00447335)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: PACAP / 統合失調症 / miRNA / 樹状突起スパイン / 神経回路 / 精神疾患 / マイクロRNA

Outline of Final Research Achievements

In this study, we showed that PACAP significantly increased the number of PSD-95-positive spines with juxtapositioned synaptophysin-positive presynaptic terminals. We also showed that PACAP significantly increased the biotinylated NR1 and NR2B in the primary cultured hippocampal neurons, suggesting that surface expression of the NMDA receptor is increased by PACAP. On the other hand, we found that the density of PSD-95- positive spines with juxtapositioned synaptophysin-positive presynaptic terminals was significantly low in the primary cultured hippocampal neurons from PACAP deficient mice compared with WT mice.
Furthermore, viral miR-132 overexpression reversed the reduction in the CA1 region of hippocampal spinal density in the PACAP deficient mice. These results indicate that PACAP signaling plays a critical role in spine morphogenesis possibly via miR-132.

Academic Significance and Societal Importance of the Research Achievements

これらの成果は，統合失調症様の精神行動異常を示すPACAP欠損マウスにおける海馬CA1でのスパインの数の低下が，特定のmiRNAにより改善することを示唆するものであり，統合失調症の病態メカニズムにつながるものであると考えられる．本研究は統合失調症の治療にむけた創薬のための基礎データを提供できるという点からも重要である．

Research Products

• [Int'l Joint Research] UCLA(米国)
• [Journal Article] Whole-brain block-face serial microscopy tomography at subcellular resolution using FAST. (2019)
  • Author(s): Seiriki K, Kasai A, Nakazawa T, Niu M, Naka Y, Tanuma M, Igarashi H, Yamaura K, Hayata-Takano A, Ago Y, Hashimoto H.
  • Journal Title: Nat Protoc. Volume: 印刷中 Issue: 5 Pages: 1509-1529
  • DOI: 10.1038/s41596-019-0148-4
  • Peer Reviewed / Open Access
• [Journal Article] Pituitary adenylate cyclase-activating polypeptide modulates dendritic spine maturation and morphogenesis via microRNA-132 upregulation. (2019)
  • Author(s): Hayata-Takano A, Kamo T, Kijima H, Seiriki K, Ogata K, Ago Y, Nakazawa T, Shintani Y, Higashino K, Nagayasu K, Shintani N, Kasai A, Waschek JA, Hashimoto H.
  • Journal Title: J Neurosci. Volume: 印刷中 Issue: 22 Pages: 4208-4220
  • DOI: 10.1523/jneurosci.2468-18.2019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] β-Arrestin1 and 2 differentially regulate PACAP-induced PAC1 receptor signaling and trafficking. (2018)
  • Author(s): Shintani Y, Hayata-Takano A, Moriguchi K, Nakazawa T, Ago Y, Kasai A, Seiriki K, Shintani N, Hashimoto H.
  • Journal Title: PLoS One Volume: 13 Issue: 5 Pages: e0196946-e0196946
  • DOI: 10.1371/journal.pone.0196946
  • Peer Reviewed / Open Access
• [Journal Article] Pathophysiological implication of the VPAC2 receptor in psychiatric disorders (2018)
  • Author(s): 吾郷由希夫、早田敦子、橋本均
  • Journal Title: Folia Pharmacologica Japonica Volume: 151 Issue: 6 Pages: 249-253
  • DOI: 10.1254/fpj.151.249
  • NAID: 130007394764
  • ISSN: 0015-5691, 1347-8397
• [Journal Article] Targeted knockdown of the mitochondria-localized protein p13 protects against experimental parkinsonism (2018)
  • Author(s): Inoue N, Ogura S, Kasai A, Nakazawa T, Ikeda K, Higashi S, Isotani A, Baba K, Mochizuki H, Fujimura H, Ago Y, Hayata-Takano A, Seiriki K, Shintani N, Hashimoto H
  • Journal Title: EMBO Reports Volume: 19(3) Issue: 3
  • DOI: 10.15252/embr.201744860
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Unbiased compound screening with a reporter gene assay highlights the role of p13 in the cardiac cellular stress response (2018)
  • Author(s): Inoue N, Hirouchi T, Kasai A, Higashi S, Hiraki N, Tanaka S, Nakazawa T, Nunomura K, Lin B, Omori A, Hayata-Takano A, Kim YJ, Doi T, Baba A, Hashimoto H, Shintani N
  • Journal Title: Biochem Biophys Res Commun. Volume: 495(2) Issue: 2 Pages: 1992-1997
  • DOI: 10.1016/j.bbrc.2017.11.116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impaired extinction of cued fear memory and abnormal dendritic morphology of the prelimbic and infralimbic cortices in VPAC2 receptor (VIPR2)-deficient mice (2017)
  • Author(s): Ago Y, Hayata-Takano A, Kawanai T, Yamauchi R, Takeuchi S, Cushman JD, Rajbhandari AK, Fanselow MS, Hashimoto H, Waschek JA
  • Journal Title: Neurobiology of Learning and Memory Volume: 145 Pages: 222-231
  • DOI: 10.1016/j.nlm.2017.10.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High-speed and scalable whole-brain imaging in rodents and primates (2017)
  • Author(s): Seiriki K, Kasai A, Hashimoto T, Schulze W, Niu M, Yamaguchi S, Nakazawa T, Inoue K, Uezono S, Takada M, Naka Y, Igarashi H, Tanuma M, Waschek JA, Ago Y, Tanaka KF, Hayata-Takano A, Nagayasu K, Shintani N, Hashimoto R, Kunii Y, Hino M, Matsumoto J, Yabe H, Nagai T, Fujita K, Matsuda T, Takuma K, Baba A, Hashimoto H
  • Journal Title: Neuron Volume: 94 Issue: 6 Pages: 1085-1100
  • DOI: 10.1016/j.neuron.2017.05.017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Differential gene expression profiles in neurons generated from lymphoblastoid B-cell line-derived iPS cells from monozygotic twin cases with treatment-resistant schizophrenia and discordant responses to clozapine. (2017)
  • Author(s): Nakazawa T, Kikuchi M, Ishikawa M, Yamamori H, Nagayasu K, Matsumoto T, Fujimoto M, Yasuda Y, Fujiwara M, Okada S, Matsumura K, Kasai A, Hayata-Takano A, Shintani N, Numata S, Takuma K, Akamatsu W, Okano H, Nakaya A, Hashimoto H, Hashimoto R.
  • Journal Title: Schizophr Res. Volume: 181 Pages: 75-82
  • DOI: 10.1016/j.schres.2016.10.012
  • NAID: 120007037467
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 分子から迫る神経薬理学 神経ペプチドPACAPおよびその受容体をターゲットとした臨床応用 (2017)
  • Author(s): 早田敦子, 吾郷由希夫, 橋本均
  • Journal Title: Clinical Neuroscience Volume: 35(10) Pages: 1150-1151
• [Journal Article] 分子から迫る神経薬理学 神経ペプチドPACAPおよびその受容体の発現分布と生理的作用 (2017)
  • Author(s): 早田敦子, 吾郷由希夫, 橋本均
  • Journal Title: Clinical Neuroscience Volume: 35(9) Pages: 1034-1036
• [Journal Article] 分子から迫る神経薬理学 神経ペプチドPACAPおよびその受容体の種類と構造 (2017)
  • Author(s): 早田敦子, 吾郷由希夫, 橋本均
  • Journal Title: Clinical Neuroscience Volume: 35(8) Pages: 912-913
• [Journal Article] Double In situ Hybridization for MicroRNAs and mRNAs in Brain Tissues. (2016)
  • Author(s): Kasai A, Kakihara S, Miura H, Okada R, Hayata-Takano A, Hazama K, Niu M, Shintani N, Nakazawa T, Hashimoto H.
  • Journal Title: Front Mol Neurosci. Volume: 9 Pages: 126-126
  • DOI: 10.3389/fnmol.2016.00126
  • Peer Reviewed / Open Access
• [Journal Article] Prostaglandin D2 signaling mediated by the CRTH2 receptor is involved in MK-801-induced cognitive dysfunction. (2016)
  • Author(s): Onaka Y, Shintani N, Nakazawa T, Kanoh T, Ago Y, Matsuda T, Hashimoto R, Ohi K, Hirai H, Nagata KY, Nakamura M, Kasai A, Hayata-Takano A, Nagayasu K, Takuma K, Ogawa A, Baba A, Hashimoto H.
  • Journal Title: Behav Brain Res. Volume: 314 Pages: 477-486
  • DOI: 10.1016/j.bbr.2016.07.050
  • Peer Reviewed / Open Access
• [Journal Article] De novo POGZ mutations in sporadic autism disrupt the DNA-binding activity of POGZ (2016)
  • Author(s): Matsumura K, Nakazawa T, Nagayasu K, Gotoda-Nishimura N, Kasai A, Hayata-Takano A, Shintani N, Yamamori H, Yasuda Y, Hashimoto R, Hashimoto H.
  • Journal Title: J. Mol. Psychiatry Volume: 4 Issue: 1 Pages: 1-1
  • DOI: 10.1186/s40303-016-0016-x
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Implications of PACAP signaling in psychiatric disorders. (2016)
  • Author(s): Hashimoto H, Shintani N, Ago Y, Hayata-Takano A, Nakazawa T, Hashimoto R, Matsuzaki S, Katayama T, Tohyama M, Matsuda T, Baba A.
  • Journal Title: Pituitary Adenylate Cyclase Activating Polypeptide ― PACAP Volume: 11 Pages: 757-766
  • Peer Reviewed
• [Journal Article] Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder. (2015)
  • 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: Journal of Human Genetics Volume: 61 Issue: 3 Pages: 199-206
  • DOI: 10.1038/jhg.2015.141
  • Peer Reviewed / Open Access
• [Presentation] Prostaglandin D2 modulates neuronal morphological development via activation of DP1 receptor (2019)
  • Author(s): Hayata-Takano A., Mohri I., Okuda K., Tachibana M., Kikuchi T., Shintani Y., Nakazawa T., Taniike M., Hashimoto H.
  • Organizer: NEURO2019
• [Presentation] Mice neonatally treated with the VPAC2 receptor agonist present cognitive dysfunction specifically reverted by clozapine (2019)
  • Author(s): Takeuchi S., Yamauchi R., Kawanai T., Miyaoka T., Chen L., Hayata-takano A., Waschek JA., Nakazawa T., Takuma K., Nakagawa S., Hashimoto H., Ago Y.
  • Organizer: NEURO2019
• [Presentation] PACAP-provoked PAC1 receptor signaling and internalization through two isoform of β-arrestins dependent mechanisms (2019)
  • Author(s): Shintani Y., Hayata-Takano A., Moriguchi K., Hashimoto H.
  • Organizer: NEURO2019
• [Presentation] Involvement of miR-132 in PACAP-dependent morphological changes of dendritic spines (2018)
  • Author(s): Hayata-TakanoA., Kijima H., Kamo T., Shintani Y., Ago Y., Seiriki K., Nakazawa T., Shintani N., Hshimoto H.
  • Organizer: CINP2018
  • Int'l Joint Research
• [Presentation] PACAP-provoked PAC1 receptor signaling and internalization through two isoform of β-arrestins dependent mechanisms (2018)
  • Author(s): Shintani Y., Hayata-Takano A., Moriguchi K., Hashimoto H.
  • Organizer: International GPCR symposium
  • Int'l Joint Research
• [Presentation] An interaction between PAC1 receptor and serotonin 2A receptor involved in receptor trafficking and signal transduction (2018)
  • Author(s): Shintani Y., Hayata-Takano A., Moriguchi K., Encho N., Hashimoto H.
  • Organizer: WCP2018
  • Int'l Joint Research
• [Presentation] 統合失調症の発症脆弱性因子としてのVPAC2受容体過活性化による大脳皮質神経発達異常と認知機能障害の発現 (2018)
  • Author(s): 竹内修斗、山内良介、河内琢也、早田敦子、Waschek James、橋本均、吾郷由希夫
  • Organizer: 第61回日本神経化学会
• [Presentation] Role of the VPAC2 receptor overactivation implicated in schizophrenia susceptibility (2018)
  • Author(s): Ago Y., Hayata-Takano A., Nakazawa T., Takuma K., Hashimoto H.
  • Organizer: Oral Neuroscience2018
  • Int'l Joint Research
• [Presentation] マウス新生仔へのプロスタグランジンD2受容体DP1作動薬による神経細胞の形態や行動への影響 (2018)
  • Author(s): 早田敦子, 奥田 健太, 毛利 育子, 橘 雅弥, 新谷 勇1, 菊池 泰河, 中澤 敬信, 谷池 雅子, 橋本 均
  • Organizer: 第48回日本神経精神薬理学会
• [Presentation] ゲノムコピー数変異に着目した統合失調症の創薬研究 (2018)
  • Author(s): 吾郷由希夫, 早田敦子, 中澤敬信, 田熊一敞, 橋本 均
  • Organizer: 日本薬学会 第139年会
• [Presentation] Modeling VIPR2 linkages to schizophrenia in mice (2017)
  • Author(s): Ago Y, Hayata-Takano A, Rajbhandari A, Fanselow M, Hashimoto H, Waschek JA
  • Organizer: The 13th International Symposium on VIP, PACAP and Related Peptides
  • Int'l Joint Research
• [Presentation] プロスタグランジンD2受容体DP1を介したマウス神経細胞の形態変化の解析 (2017)
  • Author(s): 奥田健太，早田敦子，毛利育子，新谷勇介，加茂俊彦，中澤敬信，谷池雅子, 橋本均
  • Organizer: 第132回 日本薬理学会 近畿部会
• [Presentation] In vivoパーキンソン病モデルを用いたミトコンドリア局在タンパクp13の機能解析 (2017)
  • Author(s): 小椋紗恵，井上直紀，新谷紀人，笠井淳司，中澤敬信，吾郷由希夫，早田敦子，勢力薫，橋本均
  • Organizer: 生体機能と創薬シンポジウム2017
• [Presentation] β-アレスチンを介する PACAP-PAC1 シグナルの解析 (2017)
  • Author(s): 新谷勇介，早田敦子, 橋本均
  • Organizer: 第131回 日本薬理学会 近畿部会
• [Presentation] ASD-associated de novo mutations in POGZ impair the DNA-binding activity of POGZ (2016)
  • Author(s): Nakazawa T, Matsumura K, Nagayasu K, Kasai A, Hayata-Takano A, Shintani N, Takuma K, Yamamori H, Yasuda Y, Hashimoto R, Hashimoto H.
  • Organizer: The 55th Annual Meeting, ACNP
  • Place of Presentation: Florida, USA
  • Year and Date: 2016-12-04
  • Int'l Joint Research
• [Presentation] VPAC2 receptor inhibits neurite outgrowth and branching of cortical neurons by a PKA-dependent mechanism (2016)
  • Author(s): Hashimoto H, Ago Y, Hayata-Takano A, Kawanai T, Yamauchi R, Waschek JA.
  • Organizer: The 46th Annual Meeting of the Society for Neuroscience (Neuroscience 2016)
  • Place of Presentation: San Diego, California, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] 神経細胞の成熟におけるPACAPとBDNFの役割 (2016)
  • Author(s): 早田敦子, 加茂俊彦, 勢力 薫, 尾形勝弥, 中澤敬信, 吾郷由希夫, 永安一樹, 笠井淳司, 新谷紀人, 橋本 均
  • Organizer: 第59回日本神経化学会大会
  • Place of Presentation: 福岡
  • Year and Date: 2016-09-08
• [Presentation] Overactivation of the VPAC2 receptor during the early postnatal period causes prefrontal synaptic abnormalities and cognitive dysfunction in mice (2016)
  • Author(s): Ago Y, Hayata A, Kawanai T, Yamauchi R, Waschek J, Hashimoto H.
  • Organizer: The 30th CINP World Congress of Neuropsychopharmacology,
  • Place of Presentation: ソウル(韓国)
  • Year and Date: 2016-07-03
  • Int'l Joint Research
• [Presentation] マウス新生仔期のVPAC2受容体過剰活性化は感覚情報処理機能障害と認知機能障害を引き起こす (2016)
  • Author(s): 吾郷由希夫, 早田敦子, 河内琢也, 山内良介, Waschek James, 橋本 均
  • Organizer: 第46回日本神経精神薬理学会年会
  • Place of Presentation: ソウル(韓国)
  • Year and Date: 2016-07-02
• [Presentation] 認知機能制御におけるプロスタグランジンDP2受容体の役割 (2016)
  • Author(s): 新谷紀人、尾中勇祐、叶拓也、中澤敬信、吾郷由希夫、松田敏夫、橋本亮太、大井一高、平井博之、永田欽也、中村正孝、笠井淳司、早田-高野敦子、永安一樹、馬場明道、橋本均
  • Organizer: 第46回日本神経精神薬理学会年会
  • Place of Presentation: ソウル(韓国)
  • Year and Date: 2016-07-02
• [Presentation] 統合失調症におけるVIP/PACAP受容体VPAC2活性化の病態的意義 (2016)
  • Author(s): 吾郷由希夫, 河内琢也, 山内良介, 早田敦子, James Waschek, 橋本 均
  • Organizer: 第13回GPCR研究会
  • Place of Presentation: 東京
  • Year and Date: 2016-05-13
• [Presentation] 統合失調症関連遺伝子のマウス脳における発現解析 (2016)
  • Author(s): 岩田晋平，松村憲佑, 永安一樹，馬場優志，笠井淳司，早田敦子，新谷紀人，田熊一敞, 中澤敬信, 橋本均
  • Organizer: 第130回日本薬理学会近畿部会
  • Place of Presentation: 京都
• [Remarks] 大阪大学大学院 薬学研究科 神経薬理学
  • 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 附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.html
• [Remarks] 大阪大学大学院 連合小児発達学研究科 附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
• [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