Association of mental disorder and decrease of Npas4

• Project/Area Number: 26460095
• 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: HIBI YOKO 名古屋大学, 医学部附属病院, 薬剤師 (70295616)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: Neuronal PAS domain 4 / 遺伝子欠損マウス / 精神疾患 / 脳 / DNAメチル化亢進 / GABA受容体

Outline of Final Research Achievements

Neuronal PAS domain 4 (NPAS4) has recently been shown to regulate the development of GABAergic inhibitory synapses. We previously reported that Npas4 mRNA expression levels were reduced in the hippocampus of mice exposed to social isolation or restraint stress. In the present study, we suggested that restraint stress increase the DNA methylation level of Npas4 promoter region. We analyzed the effect of decrease of Npas4 expression on the function of GABA neurons. Npas4-knockout mice were impaired in pre-pulse inhibition. GABA receptors were decreased in the cerebellum of Npas4-knockout mice. The expression level of Npas4 mRNA was significantly increased after the pentylenetetrazol (PTZ) treatment. Npas4 increased Homer1a promoter activity. Npas4 function as a molecular switch to initiate homeostatic scaling and the targetinc of Npas4-Homer1a signaling may provide new approaches for the treatment of epilepsy.

Research Products

• [Journal Article] Neuronal PAS domain protein 4 (Npas4) controls neuronal homeostasis in pentylenetetrazole-induced epilepsy through the induction of Homer1a. (2017)
  • Author(s): 2.Shan W, Nagai T, Tanaka M, Itoh N, Furukawa-Hibi Y, Nabeshima T, Sokabe M, Yamada K.
  • Journal Title: J Neurochem. Volume: - Issue: 1 Pages: 19-33
  • DOI: 10.1111/jnc.14274
  • Peer Reviewed / Open Access
• [Journal Article] Behavioral impairment in SHATI/NAT8L knockout mice via dysfunction of myelination development (2017)
  • Author(s): Sumi Kazuyuki、Uno Kyosuke、Noike Hiroshi、Tomohiro Takenori、Hatanaka Yasumaru、Furukawa-Hibi Yoko、Nabeshima Toshitaka、Miyamoto Yoshiaki、Nitta Atsumi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 16872-16872
  • DOI: 10.1038/s41598-017-17151-1
  • NAID: 120006402037
  • Peer Reviewed / Open Access
• [Journal Article] Decreased DNA methylation in the Shati/Nat8l promoter in both patients with schizophrenia and a methamphetamine-induced murine model of schizophrenia-like phenotype (2016)
  • Author(s): Uno K, Kikuchi Y, Iwata M, Uehara T, Matsuoka T, Sumiyoshi T, Okamoto Y, Jinno H, Takada T, Furukawa-Hibi Y, Nabeshima T, Miyamoto Y, Nitta A
  • Journal Title: PLoS One Volume: 11 Issue: 6 Pages: e0157959-e0157959
  • DOI: 10.1371/journal.pone.0157959
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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] Conditioned medium from the stem cells of human dental pulp improves cognitive function in a mouse model of alzheimer’s disease. (2015)
  • Author(s): Mita T, Furukawa-Hibi Y, Takeuchi H, Hattori H, Yamada K, Hibi H, Ueda M, Yamamoto A.
  • Journal Title: Behav Brain Res. Volume: 293 Pages: 189-197
  • DOI: 10.1016/j.bbr.2015.07.043
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Aberrant DNA methylation is associated with a poor outcome in juvenile myelomonocytic leukemia. (2015)
  • Author(s): Sakaguchi H, Muramatsu H, Okuno Y, Makishima H, Xu Y, Furukawa-Hibi Y, Wang X, Narita A, Yoshida K, Shiraishi Y, Doisaki S, Yoshida N, Hama A, Takahashi Y, Yamada K, Miyano S, Ogawa S, Maciejewski JP, Kojima S.
  • Journal Title: PLoS One Volume: 10 Issue: 12 Pages: e0145394-e0145394
  • DOI: 10.1371/journal.pone.0145394
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Induction of neuronal axon outgrowth by Shati/Nat8l by energy metabolism in mice cultured neurons. (2015)
  • Author(s): Sumi K, Uno K, Matsumura S, Miyamoto Y, Furukawa-Hibi Y, Muramatsu S, Nabeshima T, Nitta A.
  • Journal Title: Neuroreport Volume: 26(13) Issue: 13 Pages: 740-746
  • DOI: 10.1097/wnr.0000000000000416
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Npas4 regulates Mdm2 and thus Dcx in experience-dependent olfactory bulb interneuron dendritic spine development. (2014)
  • Author(s): Yoshihara S, Takahashi H, Nishimura N, Kinoshita M, Asahina R, Kitsuki M, Tatsumi K, Furukawa-Hibi Y, Hirai H, Nagai T, Yamada K and Tsuboi A.
  • Journal Title: Cell Reports Volume: 8 Issue: 3 Pages: 843-857
  • DOI: 10.1016/j.celrep.2014.06.056
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Overexpression of Shati/Nat8l, an N-acetyltransferase, in the nucleus accumbens attenuates the response to methamphetamine via activation of group II mGluRs in mice (2014)
  • Author(s): Miyamoto Y., Ishikawa Y., Iegaki N., Sumi K., Fu K., Sato K., Furukawa-Hibi Y., Muramatsu S., Nabeshima T., Uno K., Nitta A.
  • Journal Title: Int. J. Neuropsychopharmacol. Volume: 17 Issue: 08 Pages: 1-12
  • DOI: 10.1017/s146114571400011x
  • Peer Reviewed / Open Access
• [Journal Article] Deletion of SHATI/NAT8L increases dopamine D1 receptor on the cell surface in the nucleus accumbens, accelerating methamphetamine dependence (2014)
  • Author(s): Toriumi K, Kondo M, Nagai T, Hashimoto R, Ohi K, Song Z, Tanaka J, Mouri A, Koseki T, Yamamori H, Furukawa-Hibi Y, Mamiya T, Fukushima T, Takeda M, Nitta A, Yamada K, Nabeshima T
  • Journal Title: Int J Neuropsychopharmacol Volume: 17 Issue: 03 Pages: 443-453
  • DOI: 10.1017/s1461145713001302
  • Peer Reviewed / Open Access
• [Presentation] Transcription factor Npas4 regulates the sensory experience-dependent development of dendritic spines in newborn olfactory bulb interneurons. (2015)
  • Author(s): 吉原誠一、高橋弘雄、西村信城、木下雅仁、朝比奈諒、日比陽子、永井拓、山田清文、坪井昭夫
  • Organizer: 第92回日本生理学会年会
  • Place of Presentation: 神戸ポートピア 兵庫県神戸市
  • Year and Date: 2015-03-21 – 2015-03-23
• [Presentation] Transcription factor Npas4 regulates the sensory experience-dependent development of dendritic spines in newborn olfactory bulb interneurons. (2014)
  • Author(s): 吉原誠一、高橋弘雄、西村信城、木下雅仁、朝比奈諒、日比陽子、永井拓、山田清文、坪井昭夫
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜 神奈川県横浜市
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Transcription factor Npas4 regulates the sensory experience-dependent development of dendritic spines in newborn olfactory bulb interneurons. (2014)
  • Author(s): 吉原誠一、高橋弘雄、西村信城、木下雅仁、朝比奈諒、日比陽子、永井拓、山田清文、坪井昭夫
  • Organizer: 第37回日本神経科学会大会
  • Place of Presentation: パシフィコ横浜 神奈川県横浜市
  • Year and Date: 2014-09-11 – 2014-09-13