The function and mechanism of GABAergic signaling in schizophrenia

2013 Fiscal Year Final Research Report

• Project/Area Number: 23390293
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: YAMADA Kazuo 独立行政法人理化学研究所, 脳科学総合研究センター, 副チームリーダー (10322695)
• Co-Investigator(Kenkyū-buntansha): YOSHIKAWA Takeo 独立行政法人理化学研究所, 脳科学総合研究センター, チームリーダー (30249958) ; OHNISHI Tetsuo 独立行政法人理化学研究所, 脳科学総合研究センター, 研究員 (80373281) ; MAEKAWA Motoko 独立行政法人理化学研究所, 脳科学総合研究センター, 研究員 (50435731) ; TOYOSHIMA Manabu 独立行政法人理化学研究所, 脳科学総合研究センター, 基礎科学特別研究員 (90582750)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: 脳・神経疾患 / 遺伝子 / シグナル伝達 / ゲノム / マイクロアレイ

Research Abstract

Studies have provided evidence for abnormalities of the GABAergic system in schizophrenia. Cannabinoid receptors may play a role in modulating GABAergic neurons. In this study, we have performed the genetic analysis of the GABAergic neural transmission and the cannabinoid pathway in the pathophysiology of schizophrenia.
We examined the association of genetic variation with the disease and the alteration of gene expression in post-mortem schizophrenic brain. We found the evidence that a number of the genes in these signaling pathways are related to the disease. In addition, we conducted a series of behavioral tests in knockout mice. In behavioral experiments, knockout mice of the genes have multiple schizophrenia-like defects such as hypoactivity and reduced social interaction.
The results implicate GABAergic and cannabinoid-related dysfunctions as a key component of the molecular mechanism of schizophrenia.

Research Products

• [Journal Article] Defective craniofacial development and brain function in a mouse model for depletion of intracellular inositol synthesis (2014)
  • Author(s): Ohnishi T, Murata T, Watanabe A, Hida A, Ohba H, Iwayama Y, Mishima K, Gondo Y, Yoshikawa T
  • Journal Title: J Biol Chem Volume: 289(15) Pages: 10785-10796
  • DOI: 10.1074/jbc.M113.536706
  • Peer Reviewed
• [Journal Article] 22q11.2 deletion carriers and schizophrenia-associated novel variants (2014)
  • Author(s): Balan S, Iwayama Y, Toyota T, Toyoshima M, Maekawa M, Yoshikawa T
  • Journal Title: Br J Psychiatry Volume: 204 Pages: 398-399
  • DOI: 10.1192/bjp.bp.113.138420
  • Peer Reviewed
• [Journal Article] Soft-diet feeding after weaning affects behavior in mice : Potential increase in vulnerability to mental disorders (2014)
  • Author(s): Nose-Ishibashi K, Watahiki J, Yamada K, Maekawa M, Watanabe A, Yamamoto G, Enomoto A, Matsuba Y, Nampo T, Taguchi T, Ichikawa Y, Saido TC, Mishima K, Yamaguchi Y, Yoshikawa T, Maki K
  • Journal Title: Neuroscience Volume: 263 Pages: 257-268
  • DOI: 10.1016/j.neuroscience.2013.12.065
  • Peer Reviewed
• [Journal Article] Association of decreased prefrontal hemodynamic response during a verbal fluency task with EGR3 gene polymorphism in patients with schizophrenia and in healthy individuals (2014)
  • Author(s): Nishimura Y, Takizawa R, Koike S, Kinoshita A, Satomura Y, Kawasaki S, Yamasue H, Tochigi M, Kakiuchi C, Sasaki T, Iwayama Y, Yamada K, Yoshikawa T, Kasai K
  • Journal Title: Neuroimage Volume: 85Pt1 Pages: 527-534
  • DOI: 10.1016/j.neuroimage.2013.08.021
  • Peer Reviewed
• [Journal Article] Genetic variants on 3q21 and in the Sp8 transcription factor gene (SP8) as susceptibility loci for psychotic disorders : a genetic association study (2013)
  • Author(s): Kondo K, Ikeda M, Kajio Y, Saito T, Iwayama Y, Aleksic B, Yamada K, Toyota T, Hattori E, Ujike H, Inada T, Kunugi H, Kato T, Yoshikawa T, Ozaki N, Iwata N
  • Journal Title: PLoS One Volume: 8(8) Pages: e70964
  • DOI: 10.1371/journal.pone.0070964
  • Peer Reviewed
• [Journal Article] Population-specific haplotype association of the postsynaptic density gene DLG4 with schizophrenia. in family-based association studies (2013)
  • Author(s): Balan S, Yamada K, Hattori E, Iwayama Y, Toyota T, Ohnishi T, Maekawa M, Toyoshima M, Iwata Y, Suzuki K, Kikuchi M, Yoshikawa T
  • Journal Title: PLoS One Volume: 8(7) Pages: e70302
  • DOI: 10.1371/journal.pone.0070302
  • Peer Reviewed
• [Journal Article] Lack of association of EGR2 variants with bipolar disorder in Japanese population (2013)
  • Author(s): Balan S, Yamada K, Iwayama Y, Toyota T, Ohnishi T, Maekawa M, Toyoshima M, Iwata Y, Suzuki K, Kikuchi M, Ujike H, Inada T, Kunugi H, Ozaki N, Iwata N, Nanko S, Kato T, Yoshikawa T
  • Journal Title: Gene Volume: 526(2) Pages: 246-250
  • DOI: 10.1016/j.gene.2013.05.055
  • Peer Reviewed
• [Journal Article] A population-specific uncommon variant in GRIN3A associated with schizophrenia (2013)
  • Author(s): Takata A, Iwayama Y, Fukuo Y, Ikeda M, Okochi T, Maekawa M, Toyota T, Yamada K, Hattori E, Ohnishi T, Toyoshima M, Ujike H, Inada T, Kunugi H, Ozaki N, Nanko S, Nakamura K, Mori N, Kanba S, Iwata N, Kato T, Yoshikawa T
  • Journal Title: Biol Psychiatry Volume: 73(6) Pages: 532-539
  • DOI: 10.1016/j.biopsych.2012.10.024
  • Peer Reviewed
• [Journal Article] Genetic evidence for association between NOTCH4 and schizophrenia supported by a GWAS follow-up study in a Japanese population (2013)
  • Author(s): Ikeda M, Aleksic B, Yamada K, Iwayama-Shigeno Y, Matsuo K, Numata S, Watanabe Y, Ohnuma T, Kaneko T, Fukuo Y, Okochi T, Toyota T, Hattori E, Shimodera S, Itakura M, Nunokawa A, Shibata N, Tanaka H, Yoneda H, Arai H, Someya T, Ohmori T, Yoshikawa T, Ozaki N, Iwata N
  • Journal Title: Mol Psychiatry Volume: 18(6) Pages: 636-638
  • DOI: 10.1038/mp.2012.74
  • Peer Reviewed
• [Journal Article] Association study of the KCNJ3 gene as a susceptibility candidate for schizophrenia in the Chinese population (2012)
  • Author(s): Yamada K, Iwayama Y, Toyota T, Ohnishi T, Ohba H, Maekawa M, Yoshikawa T
  • Journal Title: Hum Genet Volume: 131(3) Pages: 443-451
  • DOI: 10.1007/s00439-011-1089-3
  • Peer Reviewed
• [Journal Article] Ablation of Mrds1/Ofcc1 induces hyper-γ-glutamyl transpeptidasemia without abnormal head development and schizophrenia-relevant behaviors in mice (2011)
  • Author(s): Ohnishi T, Yamada K, Watanabe A, Ohba H, Sakaguchi T, Honma Y, Iwayama Y, Toyota T, Maekawa M, Watanabe K, Detera-Wadleigh SD, Wakana S, Yoshikawa T
  • Journal Title: PLoS One Volume: 6(12) Pages: e29499
  • DOI: 10.1371/journal.pone.0029499
  • Peer Reviewed
• [Journal Article] Genome-wide association study of schizophrenia in Japanese population (2011)
  • Author(s): Yamada K, Iwayama Y, Hattori E, Iwamoto K, Toyota T, Ohnishi T, Ohba H, Maekawa M, Kato T, Yoshikawa T
  • Journal Title: PLoS One Volume: 6(6) Pages: e20468
  • DOI: 10.1371/journal.pone.0020468
  • Peer Reviewed
• [Journal Article] Association study of Nogo-related genes with schizophrenia in a Japanese case-control sample (2011)
  • Author(s): Jitoku D, Hattori E, Iwayama Y, Yamada K, Toyota T, Kikuchi M, Maekawa M, Nishikawa T, Yoshikawa T
  • Journal Title: Am J Med Genet B Neuropsychiatr Genet Volume: 156B(5) Pages: 581-92
  • DOI: 10.1002/ajmg.b.31199
  • Peer Reviewed
• [Presentation] Genetic Variants on 3q21 and in Sp8 Transcription Factor Gene (SP8) as Susceptibility Loci for Psychotic Disorders : a Genetic Association Study (2013)
  • Author(s): Kondo K, Ikeda M, Yamada K, Ujike H, Inada T, Kunugi H, Kato T, Yoshikawa T, Ozaki N, Iwata N
  • Organizer: 21st World Congress of Psychiatric Genetics
  • Place of Presentation: Boston, USA
  • Year and Date: 20131017-21
• [Presentation] Disturbed Gene Expression and Behavioral Defects Reminiscent of Scizophrenia in Mice Deficient in Disc-M, A Gene Encoding a Transcriptional Regulator (2013)
  • Author(s): Ohnishi T, Watanabe A, Yamada K, Arima F, Kurokawa R, Iwayama Y, Arai M, Ohba H, Toyoshima M, Ichikawa T, Miyashita M, ManabeT, Hosoya T, Itokawa M, Yoshikawa T
  • Organizer: Society of Biological Psychiatry 2013 Annual Meeting
  • Place of Presentation: San Francisco, USA
  • Year and Date: 20130516-18
• [Presentation] Confirmation of shared genetic risk between schizophrenia and bipolar disorder; a replication study of schizophrenia SNP with bipolar sample (2013)
  • Author(s): Kondo K, Ikeda M, Saito T, Kajio Y, Fukuo Y, Inada T, Ujike H, Kunugi H, Kato T, Yoshikawa T, Ozaki N, Iwata N
  • Organizer: 11th World Congress of Biological Psychiatry
  • Place of Presentation: 京都市, 京都府
  • Year and Date: 2013-06-25
• [Presentation] PAPST1遺伝子と統合失調症との関連研究 (Genetic assciation study of PAPST1 with schizophrenia) (2013)
  • Author(s): 治徳大介, 山本直樹, 岩山佳美, 吉川武男, 上里彰仁, 車地暁生, 西川徹
  • Organizer: 日本神経科学学会, 日本神経化学会, 日本神経回路学会
  • Place of Presentation: 京都市, 京都府
  • Year and Date: 2013-06-21
• [Presentation] ヒト精神疾患のモデルと思われる遺伝子改変マウスからヒト遺伝学的解析に発展させる場合に考えること (2013)
  • Author(s): 吉川武男
  • Organizer: 日本神経科学学会, 日本神経化学会, 日本神経回路学会
  • Place of Presentation: 京都市, 京都府
  • Year and Date: 2013-06-21
• [Presentation] ポストGWAS 時代の精神疾患遺伝研究 (2012)
  • Author(s): 高田 篤, 加藤 忠史, 吉川武男
  • Organizer: 第34回日本生物学的精神医学会
  • Place of Presentation: 神戸市, 兵庫県
  • Year and Date: 2012-09-28
• [Presentation] Multiple behavioral deficits reminiscent of schizophrenia in mice deficient in DISC-M (disrupted in schizophrenia matsuzawa), a gene encoding a transcriptional regulator (2012)
  • Author(s): Ohnishi T, Watanabe A, Yamada K, Ohba H, Arai M, Ichikawa C, Toyoshima M, Iwayama Y, Miyashita M, Itokawa M, Yoshikawa T
  • Organizer: 28th CINP World Congress of Neuropsychoparmacology
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2012-06-05
• [Presentation] 統合失調症 GABA 仮説の遺伝学的検証およびマウスにおける評価 (2012)
  • Author(s): 吉川武男
  • Organizer: Conference for Laboratory Animal Sciences and Technologies, KYUSHU 2012
  • Place of Presentation: 別府市, 大分県
  • Year and Date: 2012-05-25
• [Presentation] 統合失調症関連遺伝子 DISM-M が制御する遺伝子ネットワークの同定 (2012)
  • Author(s): 大西哲生, 渡邉 明子, 大羽 尚子, 豊島学, 山田 一之, 新井 誠, 市川 智恵, 岩山 佳美, 宮下 光弘, 糸川 昌成, 吉川武男
  • Organizer: 第7回日本統合失調症学会
  • Place of Presentation: 名古屋市, 愛知県
  • Year and Date: 2012-03-17
• [Presentation] 統合失調症と Nogo 関連遺伝子の遺伝子関連研究 (2011)
  • Author(s): 治徳 大介, 服部 栄治, 豊田 倫子, 山田和男, 吉川武男
  • Organizer: 第107回日本精神神経学会学術総会
  • Place of Presentation: 港区, 東京都
  • Year and Date: 20111026-27
• [Presentation] Genetic Association Study of Multiple GABA-related Genes with Schizophrenia (2011)
  • Author(s): Yamada K
  • Organizer: 2nd Asian College of Neuropsychopharmacology
  • Place of Presentation: Seoul, Korea
  • Year and Date: 20110923-24
• [Presentation] 統合失調症脆弱性形成におけるエピジェネティック修飾の関連性 (2011)
  • Author(s): 前川素子, 渡邉 明子, 大西哲生, 豊島学, 吉川武男
  • Organizer: 第44回精神神経系薬物治療研究報告会
  • Place of Presentation: 豊中市, 大阪府
  • Year and Date: 2011-12-02
• [Presentation] Genetic analysis of Schizophrenia Endophenotype (2011)
  • Author(s): Yoshikawa T
  • Organizer: Framework for Understanding Psychosis Based on Biological Treatment
  • Place of Presentation: Soul, Korea
  • Year and Date: 2011-11-05
• [Presentation] Association between EGR3 gene polymorphism and perfrontal hemodynamic response during cognitive task in patients with schizophrenia (2011)
  • Author(s): 西村 幸香, 滝沢 龍, 小池 進介, 栃木衛 , 佐 々 木 司 , 吉 川 武 男 , 笠 井 清 登
  • Organizer: 34th Annual Meeting of the Japan Neuroscience Society (Neuroscience 2011, 日本神経科学大会)
  • Place of Presentation: 横浜市, 神奈川県
  • Year and Date: 2011-09-17
• [Presentation] Mice Deficient in a Gene Encoding a Transcriptional Regulator Exhibit Multiple Behavioral Deficits Reminiscent of Schizophrenia (2011)
  • Author(s): Ohnishi T, Yamada K, Arai M, Watanabe A, Ohba H, Arima F, Ichikawa T, Ornthanalai G, Iwayama Yo, Maekawa M, Yamada K, Miyashita M, Murphy N P, Manabe T, Itokawa M, Yoshikawa T
  • Organizer: 66th Annual Meeting of society of Biological Psychiatry
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2011-05-24
• [Presentation] ゲノムワイド関連解析(GWAS)による統合失調症シグナルパスウェイの同定 (2011)
  • Author(s): 山田和男, 岩山 佳美, 服部 栄治, 岩本 和也, 豊田 倫子, 大西哲生, 大羽 尚子, 前川素子, 加藤 忠史, 吉川武男
  • Organizer: 日本生物学的精神医学会(第33回)
  • Place of Presentation: 港区, 東京都
  • Year and Date: 2011-05-22
• [Remarks] 独立行政法人 理化学研究所脳科学総合研究センター分子精神科学研究チーム
  • URL: http://www.brain.riken.jp/jp/faculty/details/54