Verification of the potential role of impaired lipid metabolism in the white matter abnormalities in schizophrenia

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K17122
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Shimamoto Chie 国立研究開発法人理化学研究所, 脳神経科学研究センター, 訪問研究員 (90755117)
• Project Period (FY): 2019-02-01 – 2023-03-31
• Keywords: 統合失調症 / 死後脳 / 脳梁 / マウス行動解析 / 脂質代謝

Outline of Final Research Achievements

We hypothesized that abnormal lipid homeostasis may underlie the pathological changes in schizophrenia. To test this hypothesis, we performed gene expression analysis using the corpora callosa from patients with schizophrenia and age- and sex-matched controls. The result shows that altered expression levels of lipid metabolism-related genes and their potential upstream transcription factors in schizophrenia. We also detected the low expression levels of microglia markers in schizophrenia. Subsequent pathway analysis identified a gene regulatory network where nuclear factor of activated T cells 2 (NFATC2) is placed most upstream. Newly generated Nfatc2 knockout mice show some schizophrenia-related behavioral abnormalities. Collectively, this study provides evidence regarding lipid abnormalities in the corpora callosa of patients with schizophrenia, and proposes the potential role of impaired NFATC2-relevant gene network and decreased microglia as its underlying mechanism.

Free Research Field

生物学的精神医学

Academic Significance and Societal Importance of the Research Achievements

本研究では、脳梁における脂質代謝に着目し、統合失調症患者でみられる脳梁のサイズやミエリン構造・機能の変化が起こる分子メカニズムを理解することを目指した。本研究により、NFATC2を起点とした遺伝子ネットワークとミクログリアの異常が関連した脂質組成変化が、統合失調症病態の形成に関与する可能性を見出した。この発見は、一部の統合失調症患者で観察される白質病変の原因となるメカニズムの理解に役立つもので、将来的に転写因子をターゲットとした新たな治療法開発の切り口になると期待できる。