Identification of the brain regions responsible for epilepsy and aggression induced by impaired synaptic transmission

• Project/Area Number: 18K07577
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: The University of Tokyo
• Principal Investigator: Miyamoto Hiroyuki 東京大学, ニューロインテリジェンス国際研究機構, 特任准教授 (90312280)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: Stxbp1 / Scn2a / シナプス伝達 / 欠神てんかん / 皮質ー線条体 / 攻撃性 / 発達障害 / てんかん / 興奮性シナプス伝達 / 皮質－線条体経路 / 皮質－線条体 / ｓｔｘｂｐ１ / Ｓｔｘｂｐ１ / Munc18-1 / 興奮性伝達

Outline of Final Research Achievements

The Munc18-1 synaptic protein (gene STXBP1) is essential for neurotransmitter release. STXBP1 gene mutations are widely observed in patients with epilepsies, although the circuit basis remains elusive. We show that mice with Stxbp1 haplodeficiency exhibit absence seizures with spike-and-wave discharges (SWDs) initiated by reduced cortical excitatory transmission into the striatum. In Stxbp1 haplodeficient mice, there is a reduction in excitatory transmission from the neocortex to striatal fast-spiking interneurons (FSIs). FSI activity transiently decreases at SWD onset, and pharmacological potentiation of AMPA receptors in the striatum suppresses SWDs. Furthermore, in wild-type mice, pharmacological inhibition of cortico-striatal FSI excitatory transmission triggers absence and convulsive seizures. These findings suggest that impaired cortico-striatal excitatory transmission is a plausible mechanism that triggers epilepsy in Stxbp1 haplodeficient mice.

Academic Significance and Societal Importance of the Research Achievements

これまで大脳皮質－視床回路が中心かつ唯一の欠神てんかんの発生機構であるという従来の説に対して、大脳皮質から大脳基底核への興奮性入力の低下によって欠神てんかんが生じ得ることが明らかとなり従来説の再考を促すことになった。今後てんかんに対する的確な診断や効果の高い治療法の開発に貢献することが期待される。またこれまで運動機能、記憶・学習などの認知機能への深い関与が知られる大脳基底核であるが、意識状態を含め脳回路全体の安定化にも寄与している側面も浮かび上がったと考える。

Research Products

• [Int'l Joint Research] Harvard university(米国)
• [Int'l Joint Research] UCSD(米国)
• [Int'l Joint Research] UCLA(米国)
• [Int'l Joint Research] Baylor College of Medicine/UCSD/Harvard university(米国)
• [Journal Article] Kv3.1 channels regulate the rate of critical period plasticity (2021)
  • Author(s): Matsuda Yoshi-Taka、Miyamoto Hiroyuki、Joho Rolf H.、Hensch Takao K
  • Journal Title: Neuroscience Research Volume: TBD Pages: 3-10
  • DOI: 10.1016/j.neures.2021.04.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Down syndrome cell adhesion molecule like-1 (DSCAML1) links the GABA system and seizure susceptibility. (2020)
  • Author(s): Hayase Y, Amano S, Hashizume K, Tominaga T, Miyamoto H, Kanno Y, Ueno-Inoue Y, Inoue T, Yamada M, Ogata S, Balan S, Hayashi K, Miura Y, Tokudome K, Ohno Y, Nishijo T, Momiyama T, Yanagawa Y, Takizawa A, Mashimo T, Serikawa T, Sekine A, Nakagawa E, Takeshita E, Yoshikawa T, Waga C, Inoue K, Goto YI, Nabeshima Y, et al.
  • Journal Title: Acta Neuropathol Commun. Volume: 8 Issue: 1 Pages: 206-206
  • DOI: 10.1186/s40478-020-01082-6
  • Peer Reviewed / Open Access
• [Journal Article] CRISPR/dCas9-based Scn1a gene activation in inhibitory neurons ameliorates epileptic and behavioral phenotypes of Dravet syndrome model mice (2020)
  • Author(s): Yamagata Tetsushi、Raveau Matthieu、Kobayashi Kenta、Miyamoto Hiroyuki、Tatsukawa Tetsuya、Ogiwara Ikuo、Itohara Shigeyoshi、Hensch Takao K.、Yamakawa Kazuhiro
  • Journal Title: Neurobiology of Disease Volume: 141 Pages: 104954-104954
  • DOI: 10.1016/j.nbd.2020.104954
  • Peer Reviewed / Open Access
• [Journal Article] Impaired cortico-striatal excitatory transmission triggers epilepsy (2019)
  • Author(s): Miyamoto Hiroyuki、Tatsukawa Tetsuya、Shimohata Atsushi、Yamagata Tetsushi、Suzuki Toshimitsu、Amano Kenji、Mazaki Emi、Raveau Matthieu、Ogiwara Ikuo、Oba-Asaka Atsuko、Hensch Takao K.、Itohara Shigeyoshi、Sakimura Kenji、Kobayashi Kenta、Kobayashi Kazuto、Yamakawa Kazuhiro
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 1917-1917
  • DOI: 10.1038/s41467-019-09954-9
  • Peer Reviewed / Open Access
• [Journal Article] Scn2a haploinsufficient mice display a spectrum of phenotypes affecting anxiety, sociability, memory flexibility and ampakine CX516 rescues their hyperactivity (2019)
  • Author(s): Tatsukawa Tetsuya、Raveau Matthieu、Ogiwara Ikuo、Hattori Satoko、Miyamoto Hiroyuki、Mazaki Emi、Itohara Shigeyoshi、Miyakawa Tsuyoshi、Montal Mauricio、Yamakawa Kazuhiro
  • Journal Title: Molecular Autism Volume: 10 Issue: 1 Pages: 1-15
  • DOI: 10.1186/s13229-019-0265-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Variant Intestinal-Cell Kinase in Juvenile Myoclonic Epilepsy (2018)
  • Author(s): Bailey Julia N.、de Nijs Laurence、Bai Dongsheng、Suzuki Toshimitsu、Miyamoto Hiroyuki、Yamakawa Kazuhiro、Lakaye Bernard、Delgado-Escueta Antonio V. et al.
  • Journal Title: New England Journal of Medicine Volume: 378 Issue: 11 Pages: 1018-1028
  • DOI: 10.1056/nejmoa1700175
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] DYRK1A-haploinsufficiency in mice causes autistic-like features and febrile seizures (2018)
  • Author(s): Raveau Matthieu、Shimohata Atsushi、Amano Kenji、Miyamoto Hiroyuki、Yamakawa Kazuhiro
  • Journal Title: Neurobiology of Disease Volume: 110 Pages: 180-191
  • DOI: 10.1016/j.nbd.2017.12.003
  • Peer Reviewed
• [Journal Article] Nav1.2 haplodeficiency in excitatory neurons causes absence-like seizures in mice (2018)
  • Author(s): Ogiwara Ikuo、Miyamoto Hiroyuki、Tatsukawa Tetsuya、Yamagata Tetsushi、Nakayama Tojo、Atapour Nafiseh、Miura Eriko、Mazaki Emi、Ernst Sara J.、Cao Dezhi、Ohtani Hideyuki、Itohara Shigeyoshi、Yanagawa Yuchio、Montal Mauricio、Yuzaki Michisuke、Inoue Yushi、Hensch Takao K.、Noebels Jeffrey L.、Yamakawa Kazuhiro
  • Journal Title: Communications Biology Volume: 1 Issue: 1 Pages: 1-16
  • DOI: 10.1038/s42003-018-0099-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 大脳皮質興奮性神経伝達の低下によって生じる欠神てんかんの新たな神経回路メカニズム (2021)
  • Author(s): 宮本浩行
  • Organizer: てんかん財団第32回研究報告会
  • Invited
• [Presentation] 乳児難治性てんかん大田原症候群：二つの独立したモデルマウスの解析による (2018)
  • Author(s): 宮本浩行
  • Organizer: てんかん治療研究振興財団 研究報告会
  • Invited
• [Book] 睡眠学 (2020)
  • Author(s): 日本睡眠学会
  • Total Pages: 712
  • Publisher: 朝倉書店
  • ISBN: 9784254301205
• [Book] 視能訓練学 (2018)
  • Author(s): 公益社団法人 日本視能訓練士協会
  • Total Pages: 440
  • Publisher: 医学書院
  • ISBN: 9784260032230