Microendophenotype of psychiatric disorders by glutamatergic signal

• Project Area: Unraveling micro-endophenotypes of psychiatric disorders at the molecular, cellular and circuit levels.
• Project/Area Number: 24116006
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Chiba University
• Principal Investigator: Kenji Hashimoto 千葉大学, 社会精神保健教育研究センター, 教授 (10189483)
• Co-Investigator(Renkei-kenkyūsha): ISHIMA Tamaki 千葉大学, 社会精神保健教育研究センター, 特任助教 (00597130)
• Research Collaborator: FUJITA Yuko 千葉大学, 社会精神保健教育研究センター, 特任助教 (40623591)
• Project Period (FY): 2012-06-28 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥72,930,000 (Direct Cost: ¥56,100,000、Indirect Cost: ¥16,830,000); Fiscal Year 2016: ¥13,910,000 (Direct Cost: ¥10,700,000、Indirect Cost: ¥3,210,000); Fiscal Year 2015: ¥13,910,000 (Direct Cost: ¥10,700,000、Indirect Cost: ¥3,210,000); Fiscal Year 2014: ¥14,040,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥3,240,000); Fiscal Year 2013: ¥13,910,000 (Direct Cost: ¥10,700,000、Indirect Cost: ¥3,210,000); Fiscal Year 2012: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
• Keywords: 脳・神経疾患 / 統合失調症 / うつ病 / ストレス / NMDA受容体 / Dセリン / ケタミン / 脳神経疾患 / 神経科学 / 薬理学 / グルタミン酸 / 脳由来神経栄養因子 / スパイン / TrkB受容体 / グルタミン酸神経系 / ＮＭＤＡ受容体 / D型セリン

Outline of Final Research Achievements

Ketamine enantiomers are the most attractive antidepressants.Repeated administration of S-ketamine, but not R-ketamine, caused the loss of parbalubumin-positive cells in the prefrontal cortex. In the social defeat stress model of depression, (2R,6R)-hydroxynorketamine, a final metabolite of R-ketamine, did not show antidepressant-like effects.
In the PolyIC model of schizophrenia, treatment of D-serine from 4-week olds to 8-week olds can prevent the onset of behavioral abnormality in adult offspring after maternal immune activation.

Research Products

• [Int'l Joint Research] Wuhan University(Ｃｈｉｎａ)
• [Int'l Joint Research] Ｎａｎｊｉｎｇ Ｕｎｉｖｅｒｓｉｔｙ(Ｃｈｉｎａ)
• [Journal Article] Reduction of dopamine D_2/3 receptor binding in the striatum after a single administration of esketamine, but not R-ketamine: a PET study in conscious monkeys. (2017)
  • Author(s): Hashimoto K, Kakiuchi T, Ohba H, Nishiyama S, Tsukada H.
  • Journal Title: Eur Arch Psychiatry Clin Neurosci Volume: 267 Issue: 2 Pages: 173-176
  • DOI: 10.1007/s00406-016-0692-7
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Effects of a single bilateral infusion of R-ketamine in the rat brain regions of a learned helplessness model of depression. (2017)
  • Author(s): Shirayama Y, Hashimoto K.
  • Journal Title: Eur Arch Psychiatry Clin Neurosci Volume: 267 Issue: 2 Pages: 177-182
  • DOI: 10.1007/s00406-016-0718-1
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Loss of parvalbumin-immunoreactivity in mouse brain regions after repeated intermittent administration of esketamine, but not R-ketamine. (2016)
  • Author(s): Yang C, Han M, Zhang JC, Ren Q, Hashimoto K.
  • Journal Title: Psychiatry Res Volume: 239 Pages: 281-283
  • DOI: 10.1016/j.psychres.2016.03.034
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression. (2016)
  • Author(s): Yang B, Zhang JC, Han M, Yao W, Yang C, Ren Q, Ma M, Chen QX, Hashimoto K.
  • Journal Title: Psychopharmacology (Berl) Volume: 233 Issue: 19-20 Pages: 3647-3657
  • DOI: 10.1007/s00213-016-4399-2
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Ketamine's antidepressant action: beyond NMDA receptor inhibition. (2016)
  • Author(s): Hashimoto K
  • Journal Title: Expert Opin Ther Targets Volume: 20 Issue: 11 Pages: 1389-1392
  • DOI: 10.1080/14728222.2016.1238899
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Regulation of glutamate transporter 1 via BDNF-TrkB signaling plays a role in the anti-apoptotic and antidepressant effects of ketamine in chronic unpredictable stress model of depression. (2016)
  • Author(s): 16.Liu WX, Wang J, Xu N, Xie ZM, Zhang GF, Jia M, Zhou ZQ, Hashimoto K, Yang, JJ.
  • Journal Title: Psychopharmacology Volume: 233 Issue: 3 Pages: 405-415
  • DOI: 10.1007/s00213-015-4128-2
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Role of hippocampal p11 in the sustained antidepressant effect of ketamine in the chronic unpredictable mild stress model. (2016)
  • Author(s): 13.Sun HL, Zhou ZQ, Zhang GF, Yang C, Wang XM, Shen JC, Hashimoto K, Yang JJ.
  • Journal Title: Translational Psychiatry Volume: 6 Issue: 2 Pages: e741-e741
  • DOI: 10.1038/tp.2016.21
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Glutamate signaling in synaptogenesis and NMDA receptors as potential therapeutic targets for psychiatric disorders. (2015)
  • Author(s): Ohgi Y, Futamura T, Hashimoto K.
  • Journal Title: Curr Mol Med Volume: 15 Pages: 206-221
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] R-ketamine: a rapid-onset and sustained anmtidepressant without psychotomimetic side effects (2015)
  • Author(s): 9.Yang C, Shirayama Y, Zhang JC, Ren Q, Yao W, Ma M, Dong C, Hashimoto K.
  • Journal Title: Translational Psychiatry Volume: 5 Issue: 9 Pages: e632-e632
  • DOI: 10.1038/tp.2015.136
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Comparison of ketamine, 7,8-dihydroxyflavone, and ANA-12 antidepressant effects in the social defeat stress model of depression. (2015)
  • Author(s): 403.Zhang, J.C., Yao, W., Dong, C., Yang, C., Ren, Q., Ma, M., Han, M., and Hashimoto, K.
  • Journal Title: Psychopharmacology Volume: 232 Issue: 23 Pages: 4325-4335
  • DOI: 10.1007/s00213-015-4062-3
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] BDNF-TrkB signaling in the nucleus accumbens shell of mice has key role in methamphetamine withdrawal symptoms. (2015)
  • Author(s): 8.Ren Q, Ma M, Yang C, Zhang JC, Yao W, Hashimoto K.
  • Journal Title: Translational Psychiatry Volume: 5 Issue: 10 Pages: e666-e666
  • DOI: 10.1038/tp.2015.157
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Antidepressant effects of TrkB ligands on depression-like behavior and dendtritic changes in the hippocampus and nucleus accumbens after inflammation. (2015)
  • Author(s): Zhang JC, Wu J, Fujita Y, Yao W, Ren Q, Yang C, Li SX, Shirayama Y, Hashimoto K
  • Journal Title: Int. J. Neuropsychopharmacol. Volume: 18 Issue: 4 Pages: 1-5
  • DOI: 10.1093/ijnp/pyu077
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Regional differences in brain-derived neurotrophic factor and dendritic spine density confer resilience to inescapable stress. (2015)
  • Author(s): Yang C, Shirayama Y, Zhang JC, Ren Q, Hashimoto K
  • Journal Title: Int. J. Neuropsychopharmacol. Volume: in press Issue: 7
  • DOI: 10.1093/ijnp/pyu121
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Effects of sodium benzoate on prepulse inhibition deficits and hyperlocomotion in mice after administration of phencyclidine. (2015)
  • Author(s): Matsuura A, Fujita Y, Iyo M, Hashimoto K
  • Journal Title: Acta. Neuropsychiatr. Volume: in press Issue: 3 Pages: 159-167
  • DOI: 10.1017/neu.2015.1
  • NAID: 120007054170
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Combination of nitrous oxide with isoflurane or scopolamine for treatment-resistant major depression. (2015)
  • Author(s): Yang C, Hashimoto K
  • Journal Title: Clin. Psychopharmacol. Neurosci. Volume: 13（1） Issue: 1 Pages: 118-120
  • DOI: 10.9758/cpn.2015.13.1.118
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] R (-)-Ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine. (2014)
  • Author(s): Ｚｈａｎｇ ＪＣ ｅｔ ａｌ．
  • Journal Title: Pharmacol. Biochem. Behav. Volume: 116 Pages: 137-143
  • DOI: 10.1016/j.pbb.2013.11.033
  • Peer Reviewed
• [Journal Article] Role of the NMDA receptor in cognitive deficits, anxiety, and depressive-like behavior in juvenile and adult mice after neonatal dexamethasone exposure. (2014)
  • Author(s): Ｌｉ ＳＸ ｅｔ ａｌ．
  • Journal Title: Ｎｅｕｒｏｂｉｏｌｏｇｙ ｏｆ Ｄｉｓｅａｓｅ Volume: 62 Pages: 124-134
  • DOI: 10.1016/j.nbd.2013.09.004
  • Peer Reviewed
• [Journal Article] Effects of antidepressants on alterations in serum cytokines and depressive-like behavior in mice after lipopolysaccharide administration. (2013)
  • Author(s): Ｏｈｇｉ Ｙ． ｅｔ ａｌ
  • Journal Title: Pharmacol. Biochem. Behav. Volume: 103 Issue: 4 Pages: 853-859
  • DOI: 10.1016/j.pbb.2012.12.003
  • Peer Reviewed
• [Journal Article] Long-lasting antidepressant action of ketamine, but not glycogen synthase kinase-3 inhibitor SB216763, in the chronic mild stress model of mice. (2013)
  • Author(s): Ｍａ ＸＣ ｅｔ ａｌ
  • Journal Title: ＰＬＯＳ ＯＮＥ Volume: 8 Issue: 2 Pages: e56053-e56053
  • DOI: 10.1371/journal.pone.0056053
  • Peer Reviewed
• [Journal Article] Old drug ifenprodil, new hope for PTSD with a history of childhood abuse. (2013)
  • Author(s): Ｈａｓｈｉｍｏｔｏ Ｋ． ｅｔ ａｌ
  • Journal Title: Ｐｓｙｃｈｏｐｈａｒｍａｃｏｌｏｇｙ Volume: 227 Issue: 2 Pages: 375-376
  • DOI: 10.1007/s00213-013-3092-y
  • Peer Reviewed
• [Journal Article] Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders (2013)
  • Author(s): Hashimoto, K., Malchow, B., Falkai, P., and Schmitt, A
  • Journal Title: Eur. Arch. Psychiatry Clin. Neurosci Volume: (in press) Issue: 5 Pages: 367-377
  • DOI: 10.1007/s00406-013-0399-y
  • Peer Reviewed
• [Journal Article] Sigma-1 receptor chaperone and brain-derived neurotrophic factor : emerging links between cardiovascular disease and depression (2013)
  • Author(s): Hashimoto K
  • Journal Title: Prog. Neurobiol. Volume: 100 Pages: 15-29
  • DOI: 10.1016/j.pneurobio.2012.09.001
  • Peer Reviewed
• [Journal Article] Understanding depression: linking brain-derived neurotrophic factor (BDNF), transglutaminase 2 (TG2), and serotonin (2013)
  • Author(s): Hashimoto K
  • Journal Title: Expert Review of Neurotherapeutics Volume: 13 Issue: 1 Pages: 5-7
  • DOI: 10.1586/ern.12.140
  • Peer Reviewed
• [Presentation] BDNF-TrkB signaling as a potential therapeutic target for methamphetamine abuse. (2015)
  • Author(s): Kenji Hashimoto
  • Organizer: ＷＰＡ Ｃｏｎｇｒｅｓｓ
  • Place of Presentation: Ｔａｉｐｅｉ， Ｔａｉｗａｎ
  • Year and Date: 2015-11-18
  • Int'l Joint Research
• [Presentation] Ｐｒｏｐｈｙｌａｃｔｉｃ ａｎｄ ｔｈｅｒａｐｅｕｔｉｃ ｅｆｆｅｃｔｓ ｏｆ ｓｕｌｆｏｒａｐｈａｎｅ－ｒｉｃｈ ｂｒｏｃｃｏｌｉ ｓｐｒｏｕｔ ｏｎ ｃｏｇｎｉｔｉｖｅ ｉｍｐａｉｒｍｅｎｔｓ ｉｎ ｓｃｈｉｚｏｐｈｒｅｎｉａ (2015)
  • Author(s): Ｋｅｎｊｉ Ｈａｓｈｉｍｏｔｏ
  • Organizer: ＷＰＡ Ｃｏｎｇｒｅｓｓ
  • Place of Presentation: Ｔａｉｐｅｉ， Ｔａｉｗａｎ
  • Year and Date: 2015-11-18
  • Int'l Joint Research
• [Presentation] Auditory sensory gating and inflammation as translational biomarkers of alpha-7 nicotinic acetylcholine receptor agonists in the treatment of neuropsychiatric disorders (2015)
  • Author(s): Kenji Hashimoto
  • Organizer: Satellite Events of Society for Neuroscience Meeting
  • Place of Presentation: Ｃｈｉｃａｇｏ， ＩＬ， ＵＳＡ
  • Year and Date: 2015-10-14
  • Int'l Joint Research
• [Presentation] うつ病治療におけるBDNF-TrkB-mTORシグナルの役割 (2015)
  • Author(s): 橋本謙二
  • 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学会
  • Place of Presentation: タワーホール船堀（東京都・江戸川区）
  • Year and Date: 2015-09-24
  • Int'l Joint Research
• [Presentation] 即効性の抗うつ薬および気分安定薬の可能性 (2015)
  • Author(s): 橋本謙二
  • Organizer: 第12回日本うつ病学会総会/第15回日本認知療法学会同時開催
  • Place of Presentation: 京王プラザホテル（東京都・新宿区）
  • Year and Date: 2015-07-17
• [Presentation] Preclinical study of D-serine signaling in schizophrenia (2015)
  • Author(s): Ｋｅｎｊｉ Ｈａｓｈｉｍｏｔｏ
  • Organizer: The 12th World Congress of Biological Psychiatry
  • Place of Presentation: Ａｔｈｅｎｅ， Ｇｒｅｅｃｅ
  • Year and Date: 2015-06-14
  • Int'l Joint Research
• [Presentation] BDNF and its precursor proBDNF as biomarkers for mood disorders. (2015)
  • Author(s): Ｋｅｎｊｉ Ｈａｓｈｉｍｏｔｏ
  • Organizer: The 12th World Congress of Biological Psychiatry
  • Place of Presentation: Ａｔｈｅｎｅ， Ｇｒｅｅｃｅ
  • Year and Date: 2015-06-14
  • Int'l Joint Research
• [Presentation] BDNF-TrkB signaling as a potential therapeutic target for methamphetamine abuse (2015)
  • Author(s): Ｋｅｎｊｉ Ｈａｓｈｉｍｏｔｏ
  • Organizer: ＷＰＡ Ｒｅｇｉｏｎａｌ Ｃｏｎｇｒｅｓｓ
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2015-06-05
  • Int'l Joint Research
• [Presentation] Role of BDNF-TrkB signaling in depression-lioke behavior in mice after withdrawal from repeated administration of methamphetamine. (2014)
  • Author(s): Ren Q, Ma M, Yang C, Yao W, Zhang JC, Hashimoto K.
  • Organizer: The 44th Annual Meeting of Society for Neuroscience
  • Place of Presentation: Convention Center (Washington DC, USA)
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] 覚せい剤の繰り返し投与後のうつ症状におけるBDNF-TrkBシグナルの役割． (2014)
  • Author(s): 任乾、馬敏、張継春、楊春、橋本謙二
  • Organizer: 平成26年度アルコール・薬物依存関連学会合同学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-10-03 – 2014-10-04
• [Presentation] Prevention of psychosis at adult by early intervention with D-serine. (2014)
  • Author(s): Hashimoto K
  • Organizer: The XVI World Congress of Psychiartry (2014WPA)
  • Place of Presentation: Convention Center (Madrid, Spain)
  • Year and Date: 2014-09-14 – 2014-09-18
• [Presentation] Clinical implications of sigma-1 receptor chaperone agonists. In Symposium 5: Sigma-1 Receptor Chaperone and Neuroprotection. (2014)
  • Author(s): Hashimoto K
  • Organizer: The 12th Meeting of the Asian-Pacific Society for Neurochemistry (2014APSN)
  • Place of Presentation: Howard Plaza Hotel (台湾高雄市)
  • Year and Date: 2014-08-24 – 2014-08-26
• [Presentation] R(-)-Ketamine shows greater potency and longer lasting antidepressant effects than S(+)-ketamine. (2014)
  • Author(s): Ｈａｓｈｉｍｏｔｏ Ｋ． ｅｔ ａｌ
  • Organizer: Miami 2014 Winter Symposium. “The Molecular Basis of Brain Disorders”
  • Place of Presentation: Ｍｉａｍｉ， ＦＬ， ＵＳＡ
• [Presentation] Effects of antidepressants on alterations in serum cytokines and depressive-like behavior in mice after lipopolysaccharide administration. (2013)
  • Author(s): Ｏｈｇｉ Ｙ． ｅｔ ａｌ．
  • Organizer: The 68th Annual Meeting of Society of Biological Psychiatry
  • Place of Presentation: Ｓａｎ Ｆｒａｎｃｉｓｃｏ， ＣＡ， ＵＳＡ
• [Presentation] Antidepressants inhibit inflammation and subsequent depressive-like behavior in mice treated with lipopolysaccharide. (2013)
  • Author(s): Ｏｈｇｉ Ｙ． ｅｔ ａｌ．
  • Organizer: The 11th World Congress of Biological Psychiatry
  • Place of Presentation: Ｋｙｏｔｏ， Ｊａｐａｎ
• [Presentation] 7,8-Dihydroxyflavone attenuates behavioral abnormalities and neurotoxicity in mice after admiistartion of methamphetamine. (2013)
  • Author(s): Ｒｅｎ Ｑ． ｅｔ ａｌ．
  • Organizer: The 43th Annual Meeting of Society for Neuroscience
  • Place of Presentation: Ｓａｎ Ｄｉｅｇｏ， ＣＡ， ＵＳＡ
• [Presentation] Antidepressant effects of TrkB ligands on depression-like behaviors and dendritic changes afrer inflamamtion. (2013)
  • Author(s): Ｚｈｎａｇ ＪＣ． ｅｔ ａｌ．
  • Organizer: The 43th Annual Meeting of Society for Neuroscience
  • Place of Presentation: Ｓａｎ Ｄｉｅｇｏ， ＣＡ， ＵＳＡ
• [Presentation] Antidepressant effects of TrkB ligands on depression-like behaviors and dendritic changes afrer inflamamtion. (2013)
  • Author(s): Ｈａｓｈｉｍｏｔｏ Ｋ． ｅｔ ａｌ．
  • Organizer: Ｔｈｅ 51st Annual Meeting of American College of Neuropsychopharmacology
  • Place of Presentation: Ｈｏｌｌｙｗｏｏｄ， ＦＬ， ＵＳＡ
• [Book] NMDA Receptors (2017)
  • Author(s): Hashimoto K
  • Total Pages: 148
  • Publisher: Springer
• [Book] SSRI: Pharmacology, Mechanisms of Action and Potential Side Effects. (2015)
  • Author(s): Albayrak Y, Hashimoto K.
  • Publisher: Nova Publsihers
• [Book] Melatonin and Neuroprotective Agents in Neuropsychiatric Disorders. (2015)
  • Author(s): Hashimoto K
  • Publisher: Spｒinger Publisher
• [Remarks] 千葉大学社会精神保健教育研究センター病態解析研究部門
  • URL: http://www.m.chiba-u.ac.jp/class/shakai/jp/byoutai/index.html
• [Remarks] 千葉大学社会精神保健教育研究センター病態解析研究部門
  • URL: http://www.m.chiba-u.ac.jp/class/shakai/jp/index.html
• [Patent(Industrial Property Rights)] R-ケタミンおよびその塩の医薬品としての応用 (2014)
  • Inventor(s): 橋本謙二
  • Industrial Property Rights Holder: 千葉大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-190066
  • Filing Date: 2014-09-12
  • Overseas
• [Patent(Industrial Property Rights)] 薬物依存症の治療薬としてのTrkB受容体拮抗薬 (2014)
  • Inventor(s): 橋本謙二
  • Industrial Property Rights Holder: 千葉大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-230008
  • Filing Date: 2014-11-12
• [Patent(Industrial Property Rights)] R-ケタミンおよびその塩の医薬品としての応用． (2013)
  • Inventor(s): 橋本謙二
  • Industrial Property Rights Holder: 千葉大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-190066
  • Filing Date: 2013-09-13