The molecular mechanism and behavioral abnormality in autism models

• Project/Area Number: 20591426
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Tokyo Metropolitan Organization for Medical Research
• Principal Investigator: YASUDA Shin Tokyo Metropolitan Organization for Medical Research, 東京都神経科学総合研究所, 研究員 (20392368)
• Co-Investigator(Kenkyū-buntansha): TAKEMIYA Takako 東京女子医科大学, 医学部, 講師 (70297547)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2008: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 脳神経疾患 / 神経科学 / 行動科学

Research Abstract

Dendritic filopodia are most abundant during periods of rapid synaptogenesis, but the number of filopodia declines thereafter. When filopodia contact presynaptic sites and form synapses, filopodia convert into dendritic spines. Normal spine formation may underlie learning and memory function, and abnormal spine formation may be associated with the pathogenesis of mental retardation and/or autism.
Mutation of tuberous sclerosis complex (TSC)-2 causes a hereditary autistic disorder in tuberous sclerosis. TSC2 has GAP activity towards small GTPase rheb, and TSC2 antagonizes mTOR pathway by stimulation of GTP hydrolysis of rheb. We analyzed Eker rats heterozygous for a mutation in the tsc2 to examine an involvement of TSC pathway in synaptogenesis. TSC2 mutation caused an inhibition of spine formation in cultured hippocampal neurons. A similar abnormality in spine formation was also observed in wild-type neuron expressed with a GTP-bound form of rheb. Thus, the excessive activation of rheb may cause the disturbance of the dendritic spinogenesis. We next attenuated such excessive activity of rheb-mTOR pathway with an mTOR inhibitor rapamycin. Rapamycin suppressed a phosphorylation of mTOR-downstream p70 S6 kinase, but did not increase the spine formation in tsc2-disrupted neurons, indicating that mTOR pathway may not be involved in spinogenesis. To identify another downstream target of rheb, we performed yeast two-hybrid screening and found a rheb-binding protein (RBP). Knockdown of RBP induced the spine formation in tsc2-mutated neurons. Conversely, overexpression of RBP abolished the maturation to spines in wild-type neurons. Furthermore, the expression of dominant-negative rheb reduced the amount of RBP, and increased dendritic spinogenesis in tsc2-mutated neurons. These results suggest that TSC2 may regulate the dendritic spine formation by controling neuronal RBP amount in a rheb-dependent manner.

Research Products

• [Journal Article] Association of RGS2 variants with panic disorder in a Japanese population. (2011)
  • Author(s): Otowa T, Shimada T, Kawamura Y, Sugaya N, Yoshida E, Inoue K, Yasuda S, Liu X, Minato T, Tochigi M, Umekage T, Kasai K, Tanii H, Okazaki Y, Kaiya H, Sasaki T
  • Journal Title: American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 156 Pages: 430-434
  • Peer Reviewed
• [Journal Article] Endothelial microsomal prostaglandin E synthase-1 facilitates neurotoxicity by elevating astrocytic Ca(2+) levels. (2011)
  • Author(s): Takemiya T, Matsumura K, Sugiura H, Yasuda S, Uematsu S, Akira S, Yamagata K
  • Journal Title: Neurochemistry international 58 Pages: 489-496
  • Peer Reviewed
• [Journal Article] p38 Map Kinase Inhibitors as Potential Therapeutic Drugs for Neural Diseases. (2011)
  • Author(s): Yasuda S, Sugiura H, Tanaka H, Takigami S, Yamagata K
  • Journal Title: Central nervous system agents in medicinal chemistry 11 Pages: 45-59
  • Peer Reviewed
• [Journal Article] Non-clustered protocadherin. (2011)
  • Author(s): Kim SY, Yasuda S, Tanaka H, Yamagata K, Kim H
  • Journal Title: Cell adhesion & migration 5 Pages: 97-105
  • Peer Reviewed
• [Journal Article] Non-clustered protocadherin. (2011)
  • Author(s): Kim SY, Yasuda S, Tanaka H, Yamagata K, Kim H
  • Journal Title: Cell adhesion & migration Volume: in press
  • Peer Reviewed
• [Journal Article] Association analysis of RGS2 variants with panic disorder in a Japanese population (2011)
  • Author(s): Otowa T, Shimada T, Kawamura Y, Sugaya N, Yoshida E, Inoue K, Yasuda S, Liu X, Minato T, Tochigi M, Umekage T, Kasai K, Tanii H, Okazaki Y, Kaiya H, Ts Sasaki T
  • Journal Title: American Journal of Medical Genetics Part B : Neuropsychiatric Genetics Volume: in press
  • Peer Reviewed
• [Journal Article] Endothelial microsomal prostaglandin E synthase-1 facilitates neurotoxicity by elevating astrocytic Ca(2+) levels. (2011)
  • Author(s): Takemiya T, Matsumura K, Sugiura H, Yasuda S, Uematsu S, Akira S, Yamagata K
  • Journal Title: Neurochemistry international Volume: 58 Pages: 489-496
  • Peer Reviewed
• [Journal Article] p38 Map Kinase Inhibitors as Potential Therapeutic Drugs for Neural Diseases. (2011)
  • Author(s): Yasuda S, Sugiura H, Tanaka H, Takigami S, Yamagata K
  • Journal Title: Central nervous system agents in medicinal chemistry Volume: 11 Pages: 45-59
  • Peer Reviewed
• [Journal Article] Replication of a genome-wide association study of panic disorder in a Japanese population. (2010)
  • Author(s): Otowa T, Tanii H, Sugaya N, Yoshida E, Inoue K, Yasuda S, Shimada T, Kawamura Y, Tochigi M, Minato T, Umekage T, Miyagawa T, Nishida N, Tokunaga K, Okazaki Y, Kaiya H, Sasaki T
  • Journal Title: Journal of human genetics 55 Pages: 91-96
  • NAID: 10030733614
  • Peer Reviewed
• [Journal Article] Endothelial microsomal prostaglandin E synthase-1 exacerbates neuronal loss induced by kainate. (2010)
  • Author(s): Takemiya T, Matsumura K, Sugiura H, Maehara M, Yasuda S, Uematsu S, Akira S, Yamagata K
  • Journal Title: Journal of neuroscience research 88 Pages: 381-390
  • Peer Reviewed
• [Journal Article] Endothelial mPGES-1 exacerbates neuronal loss induced by kainate (2010)
  • Author(s): Takemiya T, Matsumura K, Sugiura H, Maehara M, Yasuda S, Uematsu S, Akira S, Yamagata K
  • Journal Title: J Neurosci Res 88 Pages: 381-90
  • Peer Reviewed
• [Journal Article] Replication of a genome-wide association study of panic disorder in a Japanese population (2010)
  • Author(s): Otowa T, Tanii H, Sugaya N, Yoshida E, Inoue K, Yasuda S, Shimada T, Kawamura Y, Tochigi M, Minato T, Umekage T, Miyagawa T, Nishida N, Tokunaga K, Okazaki Y, Kaiya H, Sasaki T
  • Journal Title: J Hum Genet 55 Pages: 91-6
  • NAID: 10030733614
  • Peer Reviewed
• [Journal Article] Mek3 (2009)
  • Author(s): Yasuda S, Sugiura H, Yamagata K
  • Journal Title: UCSD-Nature Molecule Pages
  • Peer Reviewed
• [Journal Article] Genome-wide association study of panic disorder in the Japanese population. (2009)
  • Author(s): Otowa T, Yoshida E, Sugaya N, Yasuda S, Nishimura Y, Inoue K, Tochigi M, Umekage T, Miyagawa T, Nishida N, Tokunaga K, Tanii H, Sasaki T, Kaiya H, Okazaki Y
  • Journal Title: Journal of human genetics 54 Pages: 122-126
  • NAID: 10030729336
  • Peer Reviewed
• [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 (equal contribution)
  • Journal Title: The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 15 Pages: 90-104
  • Peer Reviewed
• [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
  • Peer Reviewed
• [Journal Article] Genome-wide association study of panic disorder in the Japanese population (2009)
  • Author(s): Otowa T, Yoshida E, Sugaya N, Yasuda S, Nishimura Y, Inoue K, Tochigi M, Umekage T, Miyagawa T, Nishida N, Tokunaga K, Tanii H, Sasaki T, Kaiya H, Okazaki Y.
  • Journal Title: J Hum Genet 54(2) Pages: 122-126
  • NAID: 10030729336
  • Peer Reviewed
• [Journal Article] ニューロンの過剰興奮後に生じるシナプス減少のメカニズム (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(5) Pages: 1257-1260
• [Presentation] 結節性硬化症における樹状突起スパイン形成異常の分子メカニズム (2010)
  • Author(s): 杉浦弘子、安田新、樋野興夫、山形要人
  • Organizer: BMB2010第33回日本分子生物学会年会・第83回日本生化学会大会 合同大会
  • Place of Presentation: 神戸コンベンションセンター
  • Year and Date: 2010-12-08
• [Presentation] カイニン酸によって生じる樹状突起スパイン減少におけるp38 MAPキナーゼの役割 (2010)
  • Author(s): 安田新、杉浦弘子、田中秀和、竹宮孝子、山形要人
  • Organizer: 第44回 日本てんかん学会
  • Place of Presentation: 岡山コンベンションセンター
  • Year and Date: 2010-10-14
• [Presentation] 結節性硬化症モデル動物における樹状突起スパイン形態異常のメカニズム (2010)
  • Author(s): 安田新、杉浦弘子、樋野興夫、山形要人
  • Organizer: Neuro2010第33回日本神経科学大会第53回日本神経化学会大会第20回日本神経回路学会大会合同大会
  • Place of Presentation: 神戸コンベンションセンター
  • Year and Date: 2010-09-02
• [Presentation] Protocadherin Arcadlin Regulates Seizure-induced Synaptic Loss by Activating p38 MAP Kinase Signaling (2010)
  • Author(s): Yasuda S, Sugiura H, Tanaka H, Takemiya T, Yamagata K
  • Organizer: 3'rd BIT Peptide and Protein Conference(Pepcon)-2010
  • Place of Presentation: 中華人民共和国北京市
  • Year and Date: 2010-03-21
• [Presentation] 結節性硬化症における樹状突起スパイン形成異常の分子メカニズム (2010)
  • Author(s): 杉浦弘子、安田新、樋野興夫、山形要人
  • Organizer: BMB2010第33回日本分子生物学会年会・第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸市
• [Presentation] カイニン酸によって生じる樹状突起スパイン減少におけるp38MAPキナーゼの役割 (2010)
  • Author(s): 安田新、杉浦弘子、田中秀和、竹宮孝子、山形要人
  • Organizer: 第44回日本てんかん学会
  • Place of Presentation: 岡山市
• [Presentation] 結節性硬化症モデル動物における樹状突起スパイン形態異常のメカニズム (2010)
  • Author(s): 安田新、杉浦弘子、樋野興夫、山形要人
  • Organizer: Neuro2010第33回日本神経科学大会第53回日本神経化学会大会第20回日本神経回路学会大会合同大会
  • Place of Presentation: 神戸市
• [Presentation] Protocadherin Arcadlin Regulates Seizure-induced Synaptic Loss by Activating p38 MAP Kinase Signaling (2010)
  • Author(s): Yasuda S, Sugiura H, Tanaka H, Takemiya T, Yamagata K
  • Organizer: 3'rd BIT Peptide and Protein Conference (Pepcon)-2010
  • Place of Presentation: 中華人民共和国、北京市
• [Presentation] 発達障害モデル動物における神経細胞樹状突起の形態変化 (2009)
  • Author(s): 瀧上周、安田新、杉浦弘子、吉村好之、竹宮孝子、山内卓、樋野興夫、山形要人
  • Organizer: 第32回 日本神経科学大会
  • Place of Presentation: 名古屋市
  • Year and Date: 2009-09-18
• [Presentation] Tsc2変異による神経細胞樹状突起形態異常の電子顕微鏡解析 (2009)
  • Author(s): 瀧上周、安田新、杉浦弘子、吉村好之、竹宮孝子、山内卓、樋野興夫、山形要人
  • Organizer: 第52回日本神経化学会
  • Place of Presentation: 渋川市
  • Year and Date: 2009-06-22
• [Presentation] 発達障害モデル動物における神経細胞樹状突起の形態変化 (2009)
  • Author(s): 瀧上周、安田新、杉浦弘子、吉村好之、竹宮孝子、山内卓、樋野興夫、山形要人
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋市
• [Presentation] Tsc2変異による神経細胞樹状突起形態異常の電子顕微鏡解析 (2009)
  • Author(s): 瀧上周、安田新、杉浦弘子、吉村好之、竹宮孝子、山内卓、樋野興夫、山形要人
  • Organizer: 第52回日本神経化学会
  • Place of Presentation: 群馬県渋川市
• [Presentation] 結節性硬化症にみられるスパイン形態異常の分子メカニズム (2008)
  • Author(s): 杉浦弘子, 安田新, 瀧上周, 吉村好之, 竹宮孝子, 山内卓, 樋野興夫, 山形要人
  • Organizer: BMB2008(日本分子生物学会年会、日本生化学会大会合同大会)
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-11
• [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: 東京
  • Year and Date: 2008-10-19
• [Presentation] Mechanism of dendritic spine abnormality in tuberous sclerosis (2008)
  • Author(s): Sugiura, H., Takigami, S., Yasuda, S., Yoshimura, Y., Takemiya, T., Yamauchi, T., Hino, O., Yamagata, K.
  • Organizer: 第51回日本神経化学会大会
  • Place of Presentation: 富山
  • Year and Date: 2008-09-12
• [Presentation] Endothelial mPGES-1 regulates Ca2+-dependent glutamate release from astrocyte via EP3 (2008)
  • Author(s): Takemiya, T., Matsumura, K., Sugiura, H., Yasuda, S., Uematsu, S., Akira, S., Yamagata, K.
  • Organizer: 第51回日本神経化学会大会
  • Place of Presentation: 富山
  • Year and Date: 2008-09-11
• [Presentation] The role of two Arcadlin splicing valiants in synaptic remodeling (2008)
  • Author(s): Yasuda, S., Sugiura, H., Maeno-Hikichi, Y., Takemiya, T., Tanaka, H., Yamagata, K.
  • Organizer: 第31回日本神経科学大会
  • Place of Presentation: 東京
  • Year and Date: 2008-07-11
• [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: 東京都新宿区
• [Presentation] The role of two Arcadlin splicing variants in synaptic remodeling (2008)
  • Author(s): Yasuda S, Sugiura H, Maeno-Hikichi Y, Takemiya T, Tanaka H, Yamagata K
  • Organizer: 第31回日本神経科学大会
  • Place of Presentation: 東京都千代田区
• [Book] Activity-dependent spine remodeling and brain disorders. (2009)
  • Author(s): Takigami S,Yasuda S, Sugiura H, Tanaka H, Yamagata K (equal contribution)
  • Publisher: (Dendritic Spines : Biochemistry, Modeling and Properties)Nova Science Publishers
• [Book] Activity-dependent spine remodeling and brain disorders. In Dendritic Spines : Biochemistry, Modeling and Properties (2009)
  • Author(s): Takigami S, Yasuda S, Sugiura H, Tanaka H, Yamagata K
  • Total Pages: 197
  • Publisher: Nova Science Publishers
• [Book] Activity-Dependent Spine Remodeling and Brain Disorders in Dendritic Spines : Biochemistry, Modeling, and Properties (2009)
  • Author(s): Takigami S., Yasuda S., Sugiura H., Tanaka H., Yamagata K.
  • Publisher: Nova Science Publishers(印刷中)
• [Book] Encyclopedia of Signaling Molecules
  • Author(s): Yasuda S, Sugiura H, Yamagata K
  • Publisher: Mek3(in press)
• [Remarks] ホームページ等
  • URL: http://researchmap.jp/saba_shibaru/
• [Remarks]
  • URL: http://researchmap.jp/saba_shibaru/
• [Remarks]
  • URL: http://jglobal.jst.go.jp/public/20090422/200901085228928457