Study on molecular mechanism for telomere shortening induced by stress exposure on schizophrenia

• Project/Area Number: 26870878
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General pharmacology; Neurochemistry/Neuropharmacology
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: TORIUMI Kazuya 公益財団法人東京都医学総合研究所, 精神行動医学研究分野, 主任研究員 (10549421)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2017: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2016: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2015: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: テロメア / 統合失調症 / 抗精神病薬 / 神経新生 / 海馬 / ストレス

Outline of Final Research Achievements

First, we found that leukocyte telomere length in Japanese patients with schizophrenia was shorter than that in healthy subjects. Second, we recognized that subchronic treatment of second-generation antipsychotics such as Risperidone (RIS), but not first-generation antipsychotics, elevated brain-derived neurotrophic factor level via 5-HT2A antagonism and increased telomerase (TERT) expression in the hippocampus. Finally, RIS improved the telomere shortening in a telomerase activity-dependent manner, the impairment of adult neurogenesis in the dentate gyrus, and some behavioral deficits shown in the mice exposed social isolation rearing stress. These findings suggested that the therapeutic effects of RIS might be mediated by telomerase activation, probably via the enhanced neurogenesis in the dentate gyrus. Furthermore, decrease of telomerase activity might be related to negative symptom, cognitive impairment, and prepulse inhibition deficits, but not positive symptom.

Research Products

• [Journal Article] Shati/Nat8l knockout mice show behavioral deficits ameliorated by atomoxetine and methylphenidate (2018)
  • Author(s): Toriumi Kazuya、Tanaka Junko、Mamiya Takayoshi、Alkam Tursun、Kim Hyoung-Chun、Nitta Atsumi、Nabeshima Toshitaka
  • Journal Title: Behavioural Brain Research Volume: 339 Pages: 207-214
  • DOI: 10.1016/j.bbr.2017.11.040
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pyridoxamine, A Novel Treatment For Schizophrenia With Enhanced Carbonyl Stress. (2018)
  • Author(s): Itokawa M, Miyashita M, Arai M, Dan T, Takahashi K, Tokunaga T, Ishimoto K, Toriumi K, Ichikawa T, Horiuchi Y, Kobori A, Usami S, Yoshikawa T, Amano N, Washizuka S, Okazaki Y, Miyata T.
  • Journal Title: Psychiatry Clin Neurosci. Volume: 72(1) Issue: 1 Pages: 35-44
  • DOI: 10.1111/pcn.12613
  • Peer Reviewed / Open Access
• [Journal Article] Protein kinase C δ gene depletion protects against methamphetamine-induced impairments in recognition memory and ERK1/2 signaling via up-regulation of glutathione peroxidase-1 gene. (2018)
  • Author(s): Tran TV, Shin EJ, Nguyen LTL, Lee Y, Kim DJ, Jeong JH, Jang CG, Nah SY, Toriumi K, Nabeshima T, Yamada K, Kim HC.
  • Journal Title: Mol Neurobiol Volume: 印刷中 Pages: 4136-4159
  • DOI: 10.1007/s12035-017-0638-8
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Foxp1 regulation of neonatal vocalizations via cortical development. (2017)
  • Author(s): Usui N, Araujo DJ, Kulkarni A, Co M, Ellegood J, Harper M, Toriumi K, Lerch JP, Konopka G.
  • Journal Title: Genes Dev Volume: 31 Issue: 20 Pages: 2039-2055
  • DOI: 10.1101/gad.305037.117
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Foxp1 in forebrain pyramidal neurons controls gene expression required for spatial learning and synaptic plasticity. (2017)
  • Author(s): Araujo DJ, Toriumi K, Escamilla C, Kulkarni A, Anderson A, Harper M, Usui N, Ellegood J, Lerch J, Birnbaum S, Tucker H, Powell C, Konopka G.
  • Journal Title: J Neurosci Volume: 2017 Issue: 45 Pages: 10917-10931
  • DOI: 10.1523/jneurosci.1005-17.2017
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Protective potential of the glutathione peroxidase-1 gene in abnormal behaviors induced by phencyclidine in mice. (2016)
  • Author(s): Tran TV, Shin EJ, Jeong JH, Lee JW, Lee Y, Jang CG, Nah SY, Lei XG, Toriumi K, Yamada K, Nabeshima T, Kim HC.
  • Journal Title: Mol Neurobiol. Volume: - Issue: 9 Pages: 7042-7062
  • DOI: 10.1007/s12035-016-0239-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The regulation of soluble receptor for AGEs contributes to carbonyl stress in schizophrenia. (2016)
  • Author(s): Miyashita M, Watanabe T, Ichikawa T, Toriumi K, Horiuchi Y, Kobori A, Kushima I, Hashimoto R, Fukumoto M, Koike S, Ujike H, Arinami T, Tatebayashi Y, Kasai K, Takeda M, Ozaki N, Okazaki Y, Yoshikawa T, Amano N, Washizuka S, Yamamoto H, Miyata T, Itokawa M, Yamamoto Y, Arai M.
  • Journal Title: Biochem Biophys Res Commun Volume: 479(3) Issue: 3 Pages: 447-452
  • DOI: 10.1016/j.bbrc.2016.09.074
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prenatal phencyclidine treatment induces behavioral deficits through impairment of GABAergic interneurons in the prefrontal cortex. (2016)
  • Author(s): Toriumi K, Oki M, Muto E, Tanaka J, Mouri A, Mamiya T, Kim HC, Nabeshima T
  • Journal Title: Psychopharmacology (Berl) Volume: 233 Issue: 12 Pages: 2373-2378
  • DOI: 10.1007/s00213-016-4288-8
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 糖化ストレスマーカーと統合失調症 (2016)
  • Author(s): 新井誠, 宮下光弘, 小堀晶子, 堀内泰江, 鳥海和也, 糸川昌成
  • Journal Title: 日本生物学的精神医学会誌 Volume: 27 Pages: 8-14
  • NAID: 130006100373
• [Journal Article] 臨床医学分野における人材育成の強化 (2016)
  • Author(s): 新井誠, 宮下光弘, 小堀晶子, 井上智子，堀内泰江, 鳥海和也, 内田美樹，畠山幸子，小幡菜々子，野原泉，糸川昌成
  • Journal Title: 日本生物学的精神医学会誌 Volume: 27 Pages: 163-167
  • NAID: 130006725645
• [Journal Article] Prenatal Nicotine Exposure Impairs the Proliferation of Neuronal Progenitors, Leading to Fewer Glutamatergic Neurons in the Medial Prefrontal Cortex. (2016)
  • Author(s): Aoyama Y, Toriumi K, Mouri A, Hattori T, Ueda E, Shimato A, Sakakibara N, Soh Y, Mamiya T, Nagai T, Kim HC, Hiramatsu M, Nabeshima T, Yamada K.
  • Journal Title: Neuropsychopharmacology Volume: 41(2) Issue: 2 Pages: 578-89
  • DOI: 10.1038/npp.2015.186
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deletion of SHATI/NAT8L decreases the N-acetylaspartate content in the brain and induces behavioral deficits, which can be ameliorated by administering N-acetylaspartate. (2015)
  • Author(s): Toriumi K, Mamiya T, Song Z, Honjo T, Watanabe H, Tanaka J, Kondo M, Mouri A, Kim HC, Nitta A, Fukushima T, Nabeshima T.
  • Journal Title: Eur Neuropsychopharmacol. Volume: 25(11) Issue: 11 Pages: 2108-17
  • DOI: 10.1016/j.euroneuro.2015.08.003
  • Peer Reviewed / Int'l Joint Research
• [Presentation] グリオキサラーゼI欠損マウス脳内のメチルグリオキサールの測定 (2017)
  • Author(s): 小池伸，西本翔一，川村久美子，鳥海和也，新井誠，小笠原裕樹
  • Organizer: 第39回日本生物学的精神医学会・第47回日本神経精神薬理学会
• [Presentation] Effect of deficiency of vitamin B6 on mouse behavior and monoaminergic system. (2017)
  • Author(s): Toriumi K, Miyashita M, Horiuchi Y, Nohara I, Obata N, Konopka G, Itokawa M, Dan T, Miyata T, Arai M.
  • Organizer: WPA XVII World Congress of Psychiatry
  • Int'l Joint Research
• [Presentation] Post-translational modification of FOXP1 in the developing brain. (2016)
  • Author(s): Usui N, Araujo D, Co M, Berto S, Harper M, Toriumi K, Tucker HO, Konopka G.
  • Organizer: 第39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: 2016-11-30
• [Presentation] High-dose pyridoxamine add-on treatement for schizophrenia with enhanced carbonyl stress. (2016)
  • Author(s): Miyashita M, Arai M, Toriumi K, Ichikawa T, Horiuchi Y, Kobori A, Takahashi K, Tokunaga T, Ishimoto K, Yuzawa H, Usami S, Yoshikawa T, Okazaki Y, Washizuka S, Amano N, Takizawa S, Miyata T, Itokawa M.
  • Organizer: Neuroscience 2016
  • Place of Presentation: San Diego Convention Center（USA）
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Effect of deficiency of vitamin B6 on mouse behavior and monoaminergic system. (2016)
  • Author(s): Toriumi K, Miyashita M, Kobori A, Horiuchi Y, Nohara I, Obata N, Itokawa M, Konopka G, Arai M.
  • Organizer: Neuroscience 2016
  • Place of Presentation: San Diego Convention Center（USA）
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Brain region-specific contributions of Foxp1 to autism-related phenotypes. (2016)
  • Author(s): Araujo DJ, Toriumi K, Escamilla CO, Harper M, Anderson AG, Berto S, Tucker HO, Powell C, Konopka G.
  • Organizer: Neuroscience 2016
  • Place of Presentation: San Diego Convention Center（USA）
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Post-translational modification of FOXP1 in the developing brain. (2016)
  • Author(s): Usui N, Araujo D, Co M, Berto S, Harper M, Toriumi K, Tucker HO, Konopka G.
  • Organizer: Neuroscience 2016
  • Place of Presentation: San Diego Convention Center（USA）
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] ビタミンB6欠乏がマウスの行動及びモノアミン神経系に与える影響について. (2016)
  • Author(s): 鳥海和也、宮下光弘、小堀晶子、堀内泰江、野原泉、小幡菜々子、糸川昌成、Genevieve Konopka、新井誠.
  • Organizer: 第59回日本神経化学会大会・第38回日本生物学的精神医学会合同年会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2016-09-08
• [Presentation] カルボニルストレスが亢進する統合失調症 に対するピリドキサミン大量療法の効果の検証． (2016)
  • Author(s): 宮下光弘，新井誠，鳥海和也，堀内泰江，市川智恵，小堀晶子，高橋克昌，徳永太郎，石本佳代，湯澤公子，宇佐美慧，吉川武男，岡崎祐士，鷲塚伸介，天野直二，滝澤俊也，宮田敏男，糸川昌成．
  • Organizer: 第59回日本神経化学会大会・第38回日本生物学的精神医学会合同年会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2016-09-08
• [Presentation] 統合失調症における新たなカルボニルストレス脆弱性. (2016)
  • Author(s): 宮下光弘，渡邉琢夫，堀内泰恵，鳥海和也，小堀晶子，吉川武男，鷲塚伸介，山本博，糸川昌成，山本靖彦，新井誠.
  • Organizer: 第112回日本精神神経学会学術総会
  • Place of Presentation: 幕張メッセ（千葉県千葉市）
  • Year and Date: 2016-06-02
• [Presentation] 統合失調症におけるカルボニルストレス脆弱性とesRAGE. (2016)
  • Author(s): 宮下光弘、渡邊琢夫、堀内泰江、鳥海和也、小堀晶子、吉川武男、鷲塚伸介、糸川昌成、山本博、新井誠
  • Organizer: 第11回日本統合失調症学会
  • Place of Presentation: ベイシア文化ホール (群馬県前橋市)
  • Year and Date: 2016-03-26
• [Presentation] 統合失調症患者由来神経細胞-グリア間代謝的相互作用の解析 (2015)
  • Author(s): 堀内泰江、鳥海和也、糸川昌成、岡野栄之、新井誠
  • Organizer: 第48回精神神経系薬物治療研究報告会
  • Place of Presentation: 千里ライフサイエンスセンター (大阪府豊中市)
  • Year and Date: 2015-12-04
• [Presentation] Pentosidene accumulation in the pathophysiology of Schizophrenia. (2015)
  • Author(s): Arai M, Horiuchi Y, Kobori A, Miyashita M, Toriumi T, Hashimoto H, Itokawa M.
  • Organizer: Society for Neuroscience 45th Annual Meeting
  • Place of Presentation: Chicago (USA)
  • Year and Date: 2015-10-21
  • Int'l Joint Research
• [Presentation] Study for the effect of carbonyl stress makers on congnitive impairment of schizophrenia. (2015)
  • Author(s): Kobori A, Hatakeyama S, Horiuchi Y, Toriumi K, Miyashita M, Itokawa M, Arai H, Arai M.
  • Organizer: Society for Neuroscience 45th Annual Meeting
  • Place of Presentation: Chicago (USA)
  • Year and Date: 2015-10-19
  • Int'l Joint Research
• [Presentation] Telomere shortening in the hippocampus is associated with negative symptom-like behavioral deficits in scizophrenia. (2015)
  • Author(s): Toriumi K, Miyashita M, Ichikawa T, Nohara I, Kobori A, Obata N, Horiuchi Y, Arai M, Hashimoto H, Itokawa M.
  • Organizer: Society for Neuroscience 45th Annual Meeting
  • Place of Presentation: Chicago (USA)
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] 統合失調症の認知機能障害に対するカルボニルストレスの影響 (2015)
  • Author(s): 小堀晶子、畠山幸子、堀内泰江、鳥海和也、宮下光弘、糸川昌成、新井平伊、新井誠
  • 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 (東京都江戸川区)
  • Year and Date: 2015-09-25
• [Presentation] 海馬のテロメア短縮は統合失調症の陰性症状及び認知機能障害に関与する (2015)
  • Author(s): 鳥海和也、宮下光正、市川智恵、新井麻友美、野原泉、小堀晶子、堀内泰江、橋本均、糸川昌成、新井誠
  • 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 (東京都江戸川区)
  • Year and Date: 2015-09-24
• [Presentation] Telomere shortening in the hippocampus is associated with the negative symtoms of schizophrenia. (2015)
  • Author(s): Toriumi K, Miyashita M, Ichikawa T, Kobori A, Arai M, Horiuchi Y, Arai M, Nohara I, Obata N, Itokawa M.
  • Organizer: 12th World Congress of Biological Psychiatry
  • Place of Presentation: Athens (Greece)
  • Year and Date: 2015-06-14
  • Int'l Joint Research
• [Presentation] Effect of carbonyl stress on congnitive impairment in schizophenia patients. (2015)
  • Author(s): Kobori A, Hatakeyama S, Arai M, Horiuchi Y, Toriumi K, Miyashita M, Arai H, Itokawa M.
  • Organizer: 12th World Congress of Biological Psychiatry
  • Place of Presentation: Athens (Greece)
  • Year and Date: 2015-06-14
  • Int'l Joint Research
• [Presentation] Telomere shortening in the hippocampus is associated with negative symptom-like behavioral deficits and cognitive impairment in schizophrenia. (2014)
  • Author(s): Kazuya Toriumi, Mitsuhiro Miyashita, Tomoe Ichikawa, Mayumi Arai, Izumi Nohara, Nanako Obata, Akiko Kobori, Yasue Horiuchi, Makoto Arai, Masanari Itokawa.
  • Organizer: 第24回日本臨床精神神経薬理学会・第44回日本神経精神薬理学会 合同年会
  • Place of Presentation: 名古屋国際会議場（愛知・名古屋市）
  • Year and Date: 2014-11-21
• [Presentation] Effect of antipsychotics on telomere length in the hippocampus. (2014)
  • Author(s): Toriumi K, Miyashita M, Ichikawa T, Kobori A, Nohara I, Arai M, Obata N, Itokawa M
  • Organizer: CINP2014
  • Place of Presentation: バンクーバー（カナダ）
  • Year and Date: 2014-06-24
• [Remarks] 公益財団法人東京都医学総合研究所 研究者実績検索 鳥海和也
  • URL: http://www.igakuken.or.jp/research_search/?authName=%E9%B3%A5%E6%B5%B7%E5%92%8C%E4%B9%9F&startyear=&endyear=2018&title=&journal=&match=0&ppage=10#
• [Remarks] 公益財団法人東京都医学総合研究所 統合失調症プロジェクト
  • URL: http://www.igakuken.or.jp/schizo-dep/index.html
• [Remarks] 公益財団法人東京都医学総合研究所 研究者実績検索 鳥海和也
  • URL: http://www.igakuken.or.jp/research_search/?authName=%E9%B3%A5%E6%B5%B7%E5%92%8C%E4%B9%9F&startyear=&endyear=2017&title=&journal=&match=0&ppage=10#
• [Remarks] 公益財団法人東京都医学総合研究所 統合失調症プロジェクト 研究業績
  • URL: http://www.igakuken.or.jp/schizo-dep/research/index.html
• [Remarks] 東京都医学総合研究所 精神行動医学研究分野 統合失調症プロジェクト
  • URL: http://www.igakuken.or.jp/schizo-dep/
• [Remarks] 東京都医学総合研究所 統合失調症プロジェクト
  • URL: http://www.igakuken.or.jp/schizo-dep/