Elucidating synaptic mechanisms and treatment of epileptic encephalopathy associated with CDKL5 mutations

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K09614
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: The University of Tokyo
• Principal Investigator: TANAKA Teruyuki 東京大学, 大学院医学系研究科(医学部), 准教授 (10246647)
• Co-Investigator(Renkei-kenkyūsha): MIZUGUCHI Masashi 東京大学, 大学院医学系研究科, 教授 (20209753) ; MANABE Toshiya 東京大学, 医科学研究所, 教授 (70251212) ; FUKAYA Masahiro 北里大学, 医学部, 講師 (10360900) ; TAKAO Keizo 富山大学, 研究推進機構研究推進総合支援センター, 講師 (80420397)
• Research Collaborator: OKUDA Kosuke 東京大学, 大学院医学系研究科, 大学院学生 ; MURAKAMI Takuto 東京大学, 大学院医学系研究科, 大学院学生
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: CDKL5 / ノックアウトマウス / 海馬 / NMDA受容体 / GluN2B / てんかん / けいれん / キナーゼ

Outline of Final Research Achievements

Mutations in the CDKL5 gene cause severe epileptic encephalopathy. Cdkl5 KO mice showed normal sensitivity to kainic acid; however, they displayed significant hyperexcitability to NMDA. Electrophysiological analysis in the hippocampus disclosed an increased ratio of NMDA/AMPA receptor-mediated excitatory postsynaptic currents (EPSCs) and a significantly larger decay time constant of NMDA receptor-mediated EPSCs in Cdkl5 KO mice. Subcellular fractionation of the hippocampus from Cdkl5 KO mice revealed a significant increase of GluN2B and SAP102 in the postsynaptic density fraction. Immunoelectron microscopic analysis of the hippocampus further confirmed postsynaptic overaccumulation of GluN2B and SAP102 in Cdkl5 KO mice. Ifenprodil abrogated the NMDA-induced hyperexcitability in Cdkl5 KO mice. These data indicate that CDKL5 plays an important role in controlling postsynaptic localization of the GluN2B-SAP102 complex in the hippocampus and thereby regulates seizure susceptibility.

Free Research Field

発達神経科学