Molecular mechanisms for the control of monoamine levels in the brain and the etiology of PTSD using serotonin-deficient mice.

2011 Fiscal Year Final Research Report

• Project/Area Number: 21500305
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neuroscience in general
• Research Institution: Tokyo Institute of Technology
• Principal Investigator: ICHINOSE Hiroshi 東京工業大学, 大学院・生命理工学研究科, 教授 (90192492)
• Co-Investigator(Kenkyū-buntansha): HIROFUMI Tokuoka 東京工業大学, 大学院・生命理工学研究科, 助教 (10452020)
• Project Period (FY): 2009 – 2011
• Keywords: 臨床神経科学

Research Abstract

We first succeeded in generating gene-targeting mice for the dihydropteridine reductase gene. The mice exhibited deficiency in the serotonin contents in the brain and PTSD-like behaviors in a battery of behavioral test. In this study, we explored the molecular mechanism for these abnormalities in the mice. We found that hyperphenylalaninemia in the mice can cause serotonin deficiency in the brain, and that a low-phenylalanine diet deteriorated the serotonin-deficiency in the mice.

Research Products

• [Journal Article] The role of tetrahydrobiopterin and catecholamines in the developmental regulation of tyrosine hydroxylase level in the brain. (2013)
  • Author(s): Homma, D., Katoh, S., Tokuoka, H. & Ichinose, H.
  • Journal Title: Journal of Neurochemistry Volume: (in press)
  • DOI: doi:10.1111/jnc.12287
  • Peer Reviewed
• [Journal Article] Nr4a receptors are essential for thymic regulatory T cell development and immune homeostasis (2013)
  • Author(s): Sekiya, T., Kashiwagi, I., Yoshida, R., Fukaya, T., Morita, R., Kimura, A., Ichinose, H., Metzger, D., Chambon, P., and Yoshimura, A.
  • Journal Title: Nature Immunology Volume: 14 Pages: 230-237
  • DOI: doi:10.1038/ni.2520
  • Peer Reviewed
• [Journal Article] Regulation of the dopaminergic system in a murine model of aromatic L-amino acid decarboxylase deficiency (2013)
  • Author(s): Lee, N.-C., Shieh, Y.-D., Chien, Y.-H., Tzen, K.-Y., Yu, I.-S., Chen, P.-W., Hu, M.-H., Hu, M., Muramatsu, S., Ichinose, H., et al.
  • Journal Title: Neurobiology of disease Volume: 52 Pages: 177-90
  • DOI: doi:10.1016/j.nbd.2012.12.005
  • Peer Reviewed
• [Journal Article] Association of monoamine-synthesizing genes with the depression tendency and personality in chronic fatigue syndrome patients (2013)
  • Author(s): Fukuda, S., Horiguchi, M., Yamaguti, K., Nakatomi, Y., Kuratsune, H., Ichinose, H., and Watanabe, Y.
  • Journal Title: Life Sciences Volume: 92 Pages: 183-18.
  • DOI: doi:10.1016/j.lfs.2012.11.016
  • Peer Reviewed
• [Journal Article] GTP cyclohydrolase 1 gene haplotypes as predictors of SSRI response in Japanese patients with major depressive disorder (2012)
  • Author(s): Kishi, T., Ichinose, H., Yoshimura, R., Fukuo, Y., Kitajima, T., Inada, T., Kunugi, H., Kato, T., Yoshikawa, T., Ujike, H., et al.
  • Journal Title: Journal of Affective Disorders Volume: 142 Pages: 315-322
  • DOI: doi:10.1016/j.jad.2012.05.004
  • Peer Reviewed
• [Journal Article] The nitric oxide-cyclic GMP pathway regulates FoxO and alters dopaminergic neuron survival in Drosophila (2012)
  • Author(s): Kanao, T., Sawada, T., Davies, S.-A., Ichinose, H., Hasegawa, K., Takahashi, R., Hattori, N., and Imai, Y
  • Journal Title: PloS one Volume: 7 Pages: e30958
  • DOI: doi:10.1371/journal.pone.0030958
  • Peer Reviewed
• [Journal Article] Recovery of neurogenic amines in phenylketonuria mice after liver-targeted gene therapy (2012)
  • Author(s): Yagi, H., Sanechika, S., Ichinose, H., Sumi-Ichinose, C., Mizukami, H., Urabe, M., Ozawa, K., and Kume, A.
  • Journal Title: Neuroreport Volume: 23 Pages: 30-34
  • DOI: doi:10.1097/WNR.0b013e32834e3a87
  • Peer Reviewed
• [Journal Article] Compensatory regulation of dopamine after ablation of the tyrosine hydroxylase gene in the nigrostriatal projection (2011)
  • Author(s): Tokuoka, H., Muramatsu, S., Sumi- Ichinose, C., Sakane, H., Kojima, M., Aso, Y., Nomura, T., Metzger, D., and Ichinose, H.
  • Journal Title: Journal of Biological Chemistry Volume: 286 Pages: 43549-43558
  • DOI: doi:10.1074/jbc.M111.284729
  • Peer Reviewed
• [Journal Article] The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells (2011)
  • Author(s): Sekiya, T., Kashiwagi, I., Inoue, N., Morita, R., Hori, S., Waldmann, H., Rudensky, A., Ichinose, H., Metzger, D., Chambon, P., et al.
  • Journal Title: Nature Communications Volume: 2 Pages: 269
  • DOI: doi:10.1038/ncomms1272
  • Peer Reviewed
• [Journal Article] Biopterin levels in the cerebrospinal fluid of patients with PARK8 (I2020T) (2011)
  • Author(s): Koshiba, S., Tokuoka, H., Yokoyama, T., Horiuchi, E., Ichinose, H., andHasegawa, K.
  • Journal Title: Journal of Neural Transmission Volume: 118 Pages: 899-903
  • DOI: doi:10.1007/s00702-011-0587-8
  • Peer Reviewed
• [Journal Article] Partial biopterin deficiency disturbs postnatal development of the dopaminergic system in the brain (2011)
  • Author(s): Homma, D., Sumi-Ichinose, C., Tokuoka, H., Ikemoto, K., Nomura, T., Kondo, K., Katoh, S., and Ichinose, H.
  • Journal Title: Journal of Biological Chemistry Volume: 286 Pages: 1445-1452
  • DOI: doi:10.1074/jbc.M110.159426
  • Peer Reviewed
• [Journal Article] Advanced research on dopamine signaling to develop drugs for the treatment of mental disorders: regulation of dopaminergic neural transmission by tyrosine hydroxylase protein at nerve terminals (2010)
  • Author(s): Sumi-Ichinose, C., Ichinose, H., Ikemoto, K., Nomura, T., and Kondo, K.
  • Journal Title: Journal of Pharmacological Science Volume: 114 Pages: 17-24
  • Peer Reviewed
• [Presentation] 家族性パーキンソン病PARK8患者の脳脊髄液中ビオプテリン代謝の解析 (2011)
  • Author(s): 一瀬宏他
  • Organizer: 第9回神経科学研究会
  • Place of Presentation: 東京
  • Year and Date: 2011-11-26
• [Presentation] モノアミン・ビオプテリン代謝改変マウスを用いたモノアミンニューロンの制御機構と発達変化の解析 (2011)
  • Author(s): 一瀬宏
  • Organizer: 第64回日本自律神経学会総会
  • Place of Presentation: 秋田市
  • Year and Date: 2011-10-28
• [Presentation] Difference in biopterin metabolism between patients with PARK8 (I2020T) and those with sporadic Parkinson's disease. (2011)
  • Author(s): Hiroshi Ichinose et al.
  • Organizer: Genomic Epidemiology of Parkinson's Disease (GEO-PD) 2011
  • Place of Presentation: Illinois, USA
  • Year and Date: 2011-09-20
• [Presentation] Tetrahydrobiopterin: As a regulator of monoamine signals in the brain (2011)
  • Author(s): Hiroshi Ichinose
  • Organizer: The 6_th International Conference of Neurons and Brain Diseases
  • Place of Presentation: 富山市
  • Year and Date: 2011-08-04
• [Presentation] ジヒドロプテリジン還元酵素ノックアウトマウスにおけるセロトニンニューロンの組織化学的解析 (2011)
  • Author(s): 原慶賢
  • Organizer: 日本ビタミン学会第63回大会
  • Place of Presentation: 広島市
  • Year and Date: 2011-06-05
• [Presentation] 慢性疲労症候群患者と健常者におけるGTPcyclohydrolaseI遺伝子多型の解析 (2011)
  • Author(s): 堀口美恵子他
  • Organizer: 第7回日本疲労学会総会学術総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2011-05-21
• [Presentation] ビオプテリンとドーパミン-線条体におけるドーパミンシグナルの調節機構 (2010)
  • Author(s): 一瀬宏
  • Organizer: 第25回大脳基底核研究会
  • Place of Presentation: 福島市
  • Year and Date: 2010-07-31