The role of a candidate gene in the etiology of autism spectrum disorder

• Project/Area Number: 24500452
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: YASUDA Shin 公益財団法人東京都医学総合研究所, 脳発達・神経再生研究分野, 研究員 (20392368)
• Co-Investigator(Kenkyū-buntansha): TOCHIGI Mamoru 帝京大学, 医学部, 准教授 (40456116)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 自閉スペクトラム症 / 樹状突起スパイン / 16p11.2微細欠失 / TAO2キナーゼ / 16p11.2症候群 / 海馬 / 16p11.2 / 自閉症スペクトラム障害 / シナプス可塑性 / カドヘリン / 自閉症モデル / 神経可塑性 / 自閉症 / 遺伝子発現

Outline of Final Research Achievements

Dendritic filopodia are most abundant during early phase of synaptogenesis, but the number of filopodia declines thereafter. When filopodia contact presynaptic sites and form synapses, filopodia convert into dendritic spines. Normal dendritic spinogenesis may be related to learning and memory function, and abnormal spine formation may cause the autistic spectrum disorder (ASD).TAO2b is a p38 MAP kinase kinase kinase, which binds to a protocadherin arcadlin at its cytoplasmic region. The gene encoding TAO2b is known to be located on chromosome 16p11.2, a region has been shown to carry substantial susceptibility to ASD. To address if TAO2b variants are associated with ASD, we sequenced TAO2b in patients and unaffected individuals. We identified two rare TAO2b variants in ASD individuals. Overexpression of each variant caused dendritic spine abnormality in cultured hippocampal neurons. We generated TAO2b knock mice. Tao2b knockout induced aberrant spine morphology and ASD-like behavior.

Research Products

• [Journal Article] Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex (2015)
  • Author(s): Hiroko Sugiura, Shin Yasuda, Shutaro Katsurabayashi, Hiroyuki Kawano, Kentaro Endo, Kotaro Takasaki, Katsunori Iwasaki, Masumi Ichikawa, Toshiyuki Kobayashi, Okio Hino and Kanato Yamagata
  • Journal Title: Nature Commun. Volume: 6 Pages: 6842-6842
  • DOI: 10.1038/ncomms7842
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dysfunction of ventrolateral prefrontal cortex underlying social anxiety disorder: a multi-channel NIRS study (2015)
  • Author(s): Yokoyama C, Kaiya H, Kumano H, Kinou M, Umekage T, Yasuda S, Takei K, Nishikawa, M, Sasaki T, Nishimura Y, Hara N, Inoue K, Kaneko Y, Suzuki S, Tanii H, Okada M, Okazaki Y
  • Journal Title: Neuroimage Clin. Volume: 8 Pages: 455-461
  • DOI: 10.1016/j.nicl.2015.05.011
  • Peer Reviewed / Open Access
• [Journal Article] Anger tendency may be associated with duration of illness in panic disorder. (2015)
  • Author(s): Sugaya N, Yoshida E, Yasuda S, Tochigi M, Takei K, Otowa T, Umekage T, Konishi Y, Sakano Y, Nomura S, Okazaki Y, Kaiya H, Tanii H, Sasaki T,
  • Journal Title: BioPsychoSocial medicine Volume: 9 Pages: 96-103
  • DOI: 10.1186/s13030-015-0035-3
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Activation of Rheb, but not of mTORC1, impairs spine synapse morphogenesis in tuberous sclerosis complex. (2014)
  • Author(s): Yasuda S, Sugiura H, Katsurabayashi S, Shimada T, Tanaka H, Takasaki K, Iwasaki K, Kobayashi T, Hino O, Yamagata K.
  • Journal Title: Science Rep. Volume: 4 Pages: 5155-5155
  • DOI: 10.1038/srep05155
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Activity-dependent regulation of dendritic spine morphology and brain diseases (2013)
  • Author(s): .山形要人，杉浦弘子，安田 新
  • Journal Title: Folia Pharmacol. Jpn. Volume: 142(3) Issue: 3 Pages: 106-111
  • DOI: 10.1254/fpj.142.106
  • NAID: 10031196209
  • ISSN: 0015-5691, 1347-8397
  • Peer Reviewed
• [Journal Article] Irritable bowel syndrome, its cognition, anxiety sensitivity, and anticipatory anxiety in panic disorder patients. (2013)
  • Author(s): Sugaya N, Yoshida E, Yasuda S, Tochigi M, Takei K, Ohtani T, Otowa T, Minato T, Umekage T, Sakano Y, Chen J, Shimada H, Nomura S, Okazaki Y, Kaiya H, Tanii H, Sasaki T
  • Journal Title: Psychiatry and clinical neurosciences Volume: 67(6) Pages: 397-404
  • DOI: 10.1111/pcn.12069
  • Peer Reviewed
• [Journal Article] Prevalence of bipolar disorder in panic disorder patients in the Japanese population. (2013)
  • Author(s): Sugaya N,Otowa T 7/18, Umekage T 9/18, Sasaki T17/18
  • Journal Title: J Affective Disorders Volume: 147(1-3) Pages: 411-415
  • DOI: 10.1016/j.jad.2012.10.014
  • Peer Reviewed
• [Journal Article] Meta-analysis of genome-wide association studies for panic disorder in Japanese population. (2012)
  • Author(s): Otowa T 1/32, Umekage T 17/32, Sasaki T 32/32
  • Journal Title: Psychiatry Volume: 13;2 Pages: 1-8
  • DOI: 10.1038/tp.2012.89
  • Peer Reviewed
• [Presentation] Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex. (2015)
  • Author(s): Yasuda S, Sugiura H, Katsurabayashi S, Kawano H, Endo K, Takasaki K, Iwasaki K, Ichikawa M, Kobayashi T, Hino O, Yamagata K
  • Organizer: 第58回日本神経化学会大会
  • Place of Presentation: 大宮ソニックシティ（埼玉県さいたま市）
  • Year and Date: 2015-09-12
• [Presentation] 結節性硬化症の樹状突起スパイン形態異常は低分子量G蛋白質Rhebの活性化により起こる (2014)
  • Author(s): 安田 新，杉浦 弘子，桂林 秀太郎，島田忠之, 田中秀和, 高崎浩太郎, 岩崎 克典，小林 敏之，樋野 興夫，山形 要人
  • Organizer: 第36回日本生物学的精神医学会、第57回日本神経化学会大会 合同大会
  • Place of Presentation: 奈良県文化会館 (奈良県、奈良市）
  • Year and Date: 2014-09-30 – 2014-10-01
• [Presentation] A novel mechanism for dendritic spine abnormality in tuberous sclerosis (2012)
  • Author(s): Yasuda S, Sugiura H, Katsurabayashi S, Iwasaki K, Hino O, Yamagata K
  • Organizer: 第55回日本神経化学会大会
  • Place of Presentation: 神戸
• [Presentation] 結節性硬化症におけるスパイン形成のmTOR非依存的機構
  • Author(s): 安田 新，杉浦 弘子，桂林 秀太郎，岩崎 克典，小林 敏之，樋野 興夫， 山形 要人
  • Organizer: 第36回日本神経科学学会、第56回日本神経化学会大会、第23回日本神経回路学会 合同大会（Neuro2013)
  • Place of Presentation: 京都国際会館
• [Book] Mek3, in Encyclopedia of Signaling Molecules (2013)
  • Author(s): Yasuda S, Sugiura H, Yamagata K
  • Total Pages: 7
  • Publisher: Springer
• [Remarks] 公益財団法人東京都医学総合研究所 シナプス可塑性プロジェクト 公式ホームページ
  • URL: http://www.igakuken.or.jp/plasticity/
• [Remarks] researchgate
  • URL: http://researchmap.jp/saba_shibaru/
• [Remarks] (公財）東京都医学総合研究所 シナプス可塑性プロジェクトHP
  • URL: http://www.igakuken.or.jp/plasticity/
• [Remarks] てんかん等脳発達障害における神経可塑性とその異常
  • URL: http://www.igakuken.or.jp/research/project/res_prj06.html