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

2020 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

神経科学

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。