Developmental brain pathophysiology at an early prenatal period in autism spectrum disorder ? gene, molecule and neuroimaging studies

2008 Fiscal Year Final Research Report

• Project/Area Number: 18209037
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Showa University (2007-2008); The University of Tokyo (2006)
• Principal Investigator: KATO Nobumasa Showa University, 医学部, 教授 (10106213)
• Co-Investigator(Renkei-kenkyūsha): SASAKI Tsukasa 東京大学, 保健センター, 教授 ; KASAI Kiyoto 東京大学, 医学部, 教授 (80322056) ; YAMAGATA Kanato 東京都神経科学総合研究所, 副参事研究員 ; SADAMATSU Miyuki 奈良県立医科大学, 准教授
• Project Period (FY): 2006 – 2008
• Keywords: 児童精神医学 / 環境変動 / 遺伝子 / 脳 / 神経 / 発生 / 分化

Research Abstract

自閉症を高率に合併することが知られている結節性硬化症の責任遺伝子TSC2に変異をもつEkerラットのスパインを超微形態学的に検討し、多数の融合した異常ミトコンドリアとシナプス未形成のフィロポディアを確認した。また、発達期に発現するarcadlinという蛋白質のスパイン制御機構を明らかにした。結節性硬化症では、TSC2-Rheb-mTORの異常が何らかのメカニズムを介してミトコンドリアの増殖あるいは融合を促進し、そのためにスパイン成熟の遅れをきたすものと考えられた。この点では、臨床遺伝学的研究により、神経接着因子(NRCAM)の遺伝子多型が自閉症と有意に関連することを見出しており、興味深い。オスのメス化作用が知られている環境ホルモンのラット新生仔期における低用量暴露が、成長後のオスのみに学習障害と多動をきたし、かつEstrogenα受容体(ERα)アンタゴニスト投与によって、環境ホルモンの脳への影響を未然に防ぐことができた。環境ホルモンの作用はラット胎仔海馬組織の初代培養系でも観察することができ、スパインの成熟遅延が見られた。このメカニズムにもERαの関与が証明された。
遺伝子解析では、7番および15番染色体長腕領域(7g,15g)上の候補遺伝子を中心に自閉症との関連を検討し、NRCAM以外にもTSC遺伝子やmaternal expression domain(MED)の一部との有意な関連を見出した。その他の部位ではオキシトシン受容体(OXTR)遺伝子の複数のSNPで自閉症症状との有意な関連を認めた。
神経画像研究では、自閉症の三主徴である、社会的相互性、コミュニケーション、固執・常同に対応する脳基盤をマルチモダリティ神経画像によって同定した。具体的には、自閉症患者の言語流暢性課題施行時の前頭葉賦活の低値とコミュニケーション障害の相関、固執の基盤となる空間的注意機能異常、社会性脳回路(下前頭回・上側頭溝など)の顕著な性差を見出した。これらの神経画像指標は、今後自閉症の三主徴に対応する遺伝子・分子基盤を効率的に見出す有力な中間表現型となる可能性がある。とくに、下前頭回は自閉症の認知異常との関連が推定されているミラーニューロンを担う部位であり、興味深い結果と考えている。現在男女差と関連する自閉症の分子機構として、性差のあるホルモンの代表であるオキシトシンに着目して研究を開始している。

Research Products

• [Journal Article] Transducing neuronal activity into dendritic spine morphology : new roles for p38 MAP kinase and N-cadherin (2009)
  • Author(s): Sugiura H, Tanaka H, Yasuda S, Takemiya T, Yamagata K
  • Journal Title: Neuroscientist 15(1) Pages: 90-104
• [Journal Article] Association of the neuronal cell adhesion molecule(NRCAM)gene variants with autism (2009)
  • Author(s): Marui T, Funatogawa I, Koishi S, Yamamoto K, Matsumoto H, Hashimoto O, Nanba E, Nishida H, Sugiyama T, Kasai K, Watanabe K, Kano Y, Kato N, Sasaki T
  • Journal Title: Int J Neuropsychopharmacol 12 Pages: 1-10
• [Journal Article] 発達精神医学の時代 : 成人自閉症スペクトラムの専門外来から見えてくるもの (2009)
  • Author(s): 加藤進昌
  • Journal Title: 精神医学 51 Pages: 312-313
• [Journal Article] Association study of the 15q11-q13 maternal expression domain in Japanese autistic patients (2008)
  • Author(s): Kato C, Tochigi M, Ohashi J, Koishi S, Kawakubo Y, Yamamoto K, Matsumoto H, Hashimoto O, Kim S-Y, Watanabe K, Kano Y, Nanba E, Kato N, Sasaki T
  • Journal Title: Am J Med Genet Part B 147B Pages: 1008-12
• [Journal Article] No association between the ryanodine receptor 3 gene and autism in a Japanese population (2008)
  • Author(s): Tochigi M, Kato C, Ohashi J, Koishi S, Kawakubo Y, Yamamoto K, Matsumoto H, Hashimoto O, Kim S-Y, Watanabe K, Kano Y, Nanba E, Kato N, Sasaki T
  • Journal Title: Psychiatr Clin Neurosci 62 Pages: 341-4
• [Journal Article] Association study of the commonly recognized breakpoints in chromosome 15q11-q13 in Japanese autistic patients (2008)
  • Author(s): Kato C, Tochigi M, Koishi S, Kawakubo Y, Yamamoto K, Matsumoto H, Hashimoto O, Kim S-Y, Watanabe K, Kano Y, Nanba E, Kato N, Sasaki T
  • Journal Title: Psychiatr Genet 18 Pages: 133-136
• [Journal Article] Effects of COX-2 inhibitors on brain diseases. (2008)
  • Author(s): Takemiya T, Yamagata K
  • Journal Title: Brain Research Journal 1(2/3) Pages: 135-164
• [Journal Article] Sex-linked neuroanatomical basis of human altruistic cooperativeness (2008)
  • Author(s): Yamasue H, Abe O, Suga M, Yamada H, Rogers MA, Aoki S, Kato N, Kasai K
  • Journal Title: Cereb Cortex 18 Pages: 2331-2340
• [Journal Article] FK506-protective effects against trimethyltin neurotoxicity in rats : Hippocampal expression analyses reveal the involvement of periarterial osteopontin (2008)
  • Author(s): Morita M, Imai H, Liu Y, Xu X, Sadamatsu M, Nakagami R, Shirakawa T, Nakano K, Kita Y, Yoshida K, Tsunashima K, and Kato N
  • Journal Title: Neuroscience 153 Pages: 1135-1145
• [Journal Article] ニューロンの過剰興奮後に生じるシナプス減-のメカニズム (2008)
  • Author(s): 田中秀和、安田新、杉浦弘子、山形要人
  • Journal Title: 実験医学 26 Pages: 1257-1260
• [Journal Article] Electrophysiological abnormalities of spatial attention in adults with autism during the gap overlap task (2007)
  • Author(s): Kawakubo Y, Kasai K, Okazaki S, Hosokawa-Kakurai M, Watanabe K, Kuwabara H, Ishijima M, Yamasue H, Iwanami A, Kato N, Maekawa H
  • Journal Title: Clin Neurophysiol 118 Pages: 1464-1471
• [Journal Article] No evidence for significant association between the GABA receptor genes in chromosome 15q11-q13 and autism in a Japanese population (2007)
  • Author(s): Tochigi M, Kato C, Koishi S, Kawakubo Y, Yamamoto K, Matsumoto H, Hashimoto O, Kim S-Y, Watanabe K, Kano Y, Nanba E, Kato N, Sasaki T
  • Journal Title: J Hum Genet 52 Pages: 985-9
• [Journal Article] Tachykinin 1(TAC1)gene SNPs and haplotypes with autism (2007)
  • Author(s): Marui T, Funatogawa I, Koishi S, Yamamoto K, Matsumoto H, Hashimoto O, Nanba E, Nishida H, Sugiyama T, Kasai K, Watanabe K, Kano Y, Kato N, Sasaki T
  • Journal Title: A case-control study. Brain Dev. 29 Pages: 510-3
• [Journal Article] Enhanced autophagic cell death in expanded polyhistidine variants of HOXA1 reduces PBX1-coupled transcriptional activity and neuronal differentiation (2007)
  • Author(s): Paraguison R, Higaki K, Yamamoto K, Matsumoto H, Sasaki T, Kato N, Nanba E
  • Journal Title: J Neurosci Res 85 Pages: 479-87
• [Journal Article] No association between the Neuronal Pentraxin II gene polymorphism and autism (2007)
  • Author(s): Marui T, Koishi S, Funatogawa I, Yamamoto K, Matsumoto H, Hashimoto O, Ishijima M, Nanba E, Nishida H, Sugiyama T, Kasai K, Watanabe E, Kano Y, Kato N, Sasaki T
  • Journal Title: Prog Neuropsycopharmacol Biol Psychiatry 31 Pages: 940-943
• [Journal Article] Thyroid hormone status of newborns in relation to in utero exposure to PCBs and hydroxylated PCB metabolites (2007)
  • Author(s): Otake T, Yoshinaga J, Enomoto T, Matsuda M, Wakimoto T, Ikegami M, Suzuki E, Naruse H, Yamanaka T, Shibuya N, Yasumizu T, Kato N
  • Journal Title: Environ Res 105 Pages: 240-246
• [Journal Article] Roles of prostaglandin synthesis in excitotoxic brain diseases (2007)
  • Author(s): Takemiya T. Matsumura K, Yamagata K
  • Journal Title: Neurochem Int 51 Pages: 112-120
• [Journal Article] Activity-Induced Protocadherin Arcadlin Regulates Dendritic Spine Number by Triggering N-Cadherin Endocytosis via TAO2beta and p38 MAP Kinases (2007)
  • Author(s): Yasuda S, Tanaka H, Sugiura H, Okamura K, Sakaguchi T, Tran U, Takemiya T, Mizoguchi A, Yagita Y, Sakurai T, De Robertis EM, Yamagata K
  • Journal Title: Neuron 56 Pages: 456-471
• [Journal Article] Temporospatial patterns of COX-2 expression and pyramidal cell degeneration in the rat hippocampus after trimethyltin administration (2007)
  • Author(s): Shirakawa T, Nakano K, Hachiya NS, Kato N, and Kaneko K
  • Journal Title: Neurosci Res 59 Pages: 117-123
• [Journal Article] Perinatal bisphenol A affects the behavior and SRC-1 expression of male pups but does not influence on the thyroid hormone receptors and its responsive gene (2007)
  • Author(s): Xu X, Liu Y, Sadamatsu M, Tsutsumi S, Akaike M, Ushijima H, Kato N
  • Journal Title: Neurosci Res 58 Pages: 149-155
• [Journal Article] Decreased prefrontal activation during letter fluency task in adults with pervasive developmental disorders : a near-infrared spectroscopy study (2006)
  • Author(s): Kuwabara H, Kasai K, Takizawa R, Kawakubo Y, Yamasue H, Rogers MA, Ishijima M, Watanabe K, Kato N
  • Journal Title: Behav Brain Res 172 Pages: 272-277
• [Journal Article] Differential expression of the CD14/TLR4 complex and inflammatory signaling molecules following i.c.v. administration of LPS (2006)
  • Author(s): Xia Y, Yamagata K, Krukoff TL
  • Journal Title: Brain Res 1095 Pages: 85-95
• [Journal Article] Prostaglandin E2 produced by late induced COX-2 stimulates hippocampal neuron loss after seizure in the CA3 region. (2006)
  • Author(s): Takemiya T, Maehara M, Matsumura K, Yasuda S, Sugiura H, Yamagata K
  • Journal Title: Neurosci Res. 56 Pages: 103-110
• [Journal Article] Serotonin transporter gene promotor polymorphism and autism : a family-based genetic association study in Japanese population (2006)
  • Author(s): Koishi S, Yamamoto K, Matsumoto H, Koishi S, Enseki Y, Oya A, Aaskura A, Aoki Y, Atsumi M, Iga T, Inomata J, Inoko H, Sasaki T, Nanba E, Kato N, Ishii T, Yamazaki K
  • Journal Title: Brain Dev 28 Pages: 257-260
• [Journal Article] Retrospective in utero exposure assessment of PCBs with the preserved umbilical cords and its application to case-control comparison (2006)
  • Author(s): Otake T, Yoshinaga J, Seki Y, Matsumura T, Watanabe K, Ishijima M, Kato N
  • Journal Title: Environ Heal Prevent Medi 11 Pages: 65-68
• [Journal Article] Review of animal models for autism : implication of thyroid hormone (2006)
  • Author(s): Sadamatsu M, Kanai H, Xu X, Liu Y, Kato N
  • Journal Title: Congenit Anom(Kyoto) 46 Pages: 1-9
• [Journal Article] 痙攣発作で誘導されるG蛋白質Rhebと結節性硬化症 (2006)
  • Author(s): 安田新、山形要人
  • Journal Title: 医学のあゆみ 217 Pages: 854-856
• [Journal Article] Fragile X carrier screening and FMR1 allele distribution in the Japanese population
  • Author(s): Otsuka S, Sakamoto Y, Siomi H, Itakura M, Yamamoto K, Matsumoto H, Sasaki T, Kato N, Nanba E
  • Journal Title: Brain Dev (in press)
• [Presentation] The broader phenotype in parents of individuals with autism spectrumdisorders (2008)
  • Author(s): Kawakubo Y, Kuwabara H, Kasai K
  • Organizer: International Meeting for Autism Research
  • Place of Presentation: London, May[Poster]
  • Year and Date: 20080515-17
• [Presentation] Neural basis of social dysfunction in autism-spectrum disorder (2008)
  • Author(s): Yamasue H, Kasai K, Kato N
  • Organizer: 13th Pacific Rim College of Psychiatrists Scientific Meeting
  • Place of Presentation: Tokyo, Japan[Symposium]
  • Year and Date: 2008-10-31
• [Presentation] 発作により発現する神経接着分子Arcadlinのてんかん病態における役割 (2008)
  • Author(s): 安田新、竹宮孝子、杉浦弘子、瀧上周、田中秀和、山形要人
  • Organizer: 第42回日本てんかん学会
  • Place of Presentation: リーガロイヤルホテル東京
  • Year and Date: 2008-10-19
• [Presentation] 発達障害の脳機能画像 (2008)
  • Author(s): 笠井清登
  • Organizer: 第10回科学技術交流フォーラム
  • Place of Presentation: 東京大学(シンポジウム)
  • Year and Date: 2008-06-17
• [Presentation] 広汎性発達障害における神経画像研究の現状と展望 (2007)
  • Author(s): 笠井清登
  • Organizer: 第37回日本臨床神経生理学会
  • Place of Presentation: ランチョンセミナー、宇都宮
  • Year and Date: 2007-11-22
• [Presentation] 自閉症スペクトラム障害の神経画像 (2007)
  • Author(s): 笠井清登、川久保友紀、桑原斉、山末英典
  • Organizer: 第30回日本神経科学大会
  • Place of Presentation: シンポジウム、横浜
  • Year and Date: 2007-09-12
• [Presentation] Assessment of prefrontal cortical function in pervasive developmental disorders using near-infrared spectroscopy (2007)
  • Author(s): Kuwabara H, Kasai K, Kawakubo Y, Kato N
  • Organizer: 13th International Congress on Europian Society for Child and Adolescent Psychiatry
  • Place of Presentation: Florence, Italy[Symposium]
  • Year and Date: 2007-08-26
• [Presentation] Environmental Disruptors hinder brain development - role of estrogen. . The 37th Annual ISPNE Conference, Hormones & Brain from cloning to clinic (2006)
  • Author(s): X Xu, Y Liu, Imai H, Sadamatsu M, Akaike M, Ushijima H, Matsuda K, Kawata M, Kato N
  • Organizer: The Netherlands, Leiden
  • Place of Presentation: [Symposium]
  • Year and Date: 20060823-26
• [Book] The modulatory role of COX-2 and prostaglandins in brain diseases, Prostaglandins (2006)
  • Author(s): Takemiya T, Yamagata K
  • Total Pages: 0(0), 63-89
  • Publisher: New Research
• [Book] Effects of COX-2 inhibitors on brain diseases (2006)
  • Author(s): Takemiya T. Yamagata K
  • Total Pages: 0(0), 47-75
  • Publisher: Trends in COX-2 inhibitor research
• [Book] Activity-dependent spine remodeling and brain disorders. "Dendritic Spines : Biochemistry, Modeling and Properties"
  • Author(s): Takigami S, Yasuda S, Sugiura H, Tanaka H. Yamagata K
  • Publisher: Nova science publishers, New York(in press)
• [Remarks] 平成19年11月16日朝日新聞(山形)
• [Remarks] 平成19年11月8日日経産業新聞(山形)
• [Remarks] 平成19年11月8-14日Yahoo! JAPANニュース(山形)他
• [Patent(Industrial Property Rights)] (2008)
  • Industrial Property Number: 特願2008-146721
  • Filing Date: 2008-06-04