Pathophysiology of glutamate excitotoxicity evaluated with MR spectroscopy

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K10329
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Radiation science
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: TAKANASHI JUNICHI 東京女子医科大学, 医学部, 教授 (00302555)
• Research Collaborator: Aoki Ichio
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: MRスペクトルスコピー / グルタミン酸 / モデルマウス / 急性脳症

Outline of Final Research Achievements

Glutamate (Glu) is a major excitatory neurotransmitter in the central nervous system, and its excess is considered to be the cause of various neurological diseases. We elucidated the pathogenesis of Glu from neurochemical analysis by MR spectroscopy (MRS) using a 7 Tesla magnet.
Glutamate transporter (GLT1) iKO mice have reduced GLT1 activity to 30-40% compared to normal, leading to accumulation of Glu in the synapse. MR spectroscopy showed an increase in glutamine (Gln) and normal Glu. The biomechanism that converts excess Glu into harmless Gln was assumed. MRS in Pnpla7 mutant mice showed low N-acetylaspartate (NAA), Cho and Glu. PNPLA7 contributes to myelination in the central nervous system, and it is considered that the defect may cause neuronal and Glu-Gln cycle abnormality. From the examination of human patients with acute encephalopathy, we found mild encephalopathy with excitotoxicity (MEEX), which shows no abnormality on MRI and transiently high Gln value.

Free Research Field

小児神経放射線

Academic Significance and Societal Importance of the Research Achievements

グルタミン酸（Glu）は中枢神経系における主要な興奮性神経伝達物質であり、その過剰は神経疾患の原因となりうる。７テスラMRI装置を用いたMR spectroscopyによる解析から、シナプス内の過剰なGluをアストロサイトで無害なグルタミンに転換させる生体防御メカニズムが示された。小児急性脳症の一部は、興奮毒性が関与する軽症脳症（mild encephalopathy with excitotoxicity [MEEX]）であり、けいれん重積型（二相性）脳症（AESD）と一連のスペクトラムを呈すると考えられる。これらの知見は興奮毒性の関与する神経疾患の診断・治療効果判定に有用である。