Electrophysiological analysis in mouse models of schizophrenia accompanied by morphological changes of dendritic spines

• Project/Area Number: 17K07068
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurophysiology / General neuroscience
• Research Institution: Gunma University
• Principal Investigator: Suzuki Norimitsu 群馬大学, 生体調節研究所, 特任講師 (10322207)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: スパイン / 統合失調症 / 電気生理 / 2光子顕微鏡 / シミュレーション

Outline of Final Research Achievements

We found extra-large (XL) spines in prefrontal cortex in mouse models of schizophrenia. Electrophysiological recordings from pyramidal cells of acute brain slice preparation revealed significant increases in excitatory postsynaptic currents in mouse models of schizophrenia. By combining activation of an individual XL spine by two-photon glutamate uncaging with measurements of synaptic and dendritic Ca events as well as whole-cell patch-clamp recording of the same neuron, we demonstrate that the relationship between spine size and the integral of the synaptic responses is steeply sigmoidal, revealing that a distinct population of XL spines can boost neuronal firing. We experimentally and theoretically observed that XL spines negatively correlated with working memory, which can contribute to psychiatric pathophysiology.

Academic Significance and Societal Importance of the Research Achievements

統合失調症モデルで見られる樹状突起スパインの形態変異（巨大スパイン）の機能解析によって、スパインサイズと統合失調症の病態生理との関連を示した報告はこれまでにない。シナプスには統合失調症関連因子が集積することが知られており、潜在的な創薬標的因子が多く存在するとされる。本研究により得られたスパインサイズと神経興奮性との関連性についての知見は、認知機能障害の理解と治療に貢献できると考えられる。

Research Products

• [Presentation] 統合失調症モデルマウスのシナプス病態の形態学的および機能的解析 (2019)
  • Author(s): 小尾紀翔、白井福寿、梅沢茉里、鈴木紀光、林（高木）朗子
  • Organizer: 第42回日本神経科学大会、第62回日本神経化学会大会
  • Int'l Joint Research
• [Presentation] Morphological and functional analysis of the DISC1 knockdown mice for understanding the relationship between synaptopathy and schizophrenia (2019)
  • Author(s): Kisho Obi, Fukutoshi Shirai, Mari Umezawa, Norimitsu Suzuki & Akiko Hayashi-Takagi
  • Organizer: The 42nd Annual Meeting of the Japan Neuroscience Society, The 62nd Annual Meeting of the Japanese Society for Neurochemistry
  • Int'l Joint Research