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Disease-relevant upregulation of P2Y1 receptor in astrocytes enhances neuronal excitability via IGFBP2

Author

Listed:
  • Eiji Shigetomi

    (University of Yamanashi
    University of Yamanashi)

  • Hideaki Suzuki

    (University of Yamanashi
    University of Yamanashi)

  • Yukiho J. Hirayama

    (University of Yamanashi)

  • Fumikazu Sano

    (University of Yamanashi
    University of Yamanashi
    University of Yamanashi)

  • Yuki Nagai

    (University of Yamanashi
    University of Yamanashi)

  • Kohei Yoshihara

    (Kyushu University)

  • Keisuke Koga

    (Kyushu University
    Hyogo College of Medicine)

  • Toru Tateoka

    (University of Yamanashi)

  • Hideyuki Yoshioka

    (University of Yamanashi)

  • Youichi Shinozaki

    (University of Yamanashi
    University of Yamanashi)

  • Hiroyuki Kinouchi

    (University of Yamanashi)

  • Kenji F. Tanaka

    (Keio University School of Medicine)

  • Haruhiko Bito

    (The University of Tokyo)

  • Makoto Tsuda

    (Kyushu University
    Kyushu University)

  • Schuichi Koizumi

    (University of Yamanashi
    University of Yamanashi)

Abstract

Reactive astrocytes play a pivotal role in the pathogenesis of neurological diseases; however, their functional phenotype and the downstream molecules by which they modify disease pathogenesis remain unclear. Here, we genetically increase P2Y1 receptor (P2Y1R) expression, which is upregulated in reactive astrocytes in several neurological diseases, in astrocytes of male mice to explore its function and the downstream molecule. This astrocyte-specific P2Y1R overexpression causes neuronal hyperexcitability by increasing both astrocytic and neuronal Ca2+ signals. We identify insulin-like growth factor-binding protein 2 (IGFBP2) as a downstream molecule of P2Y1R in astrocytes; IGFBP2 acts as an excitatory signal to cause neuronal excitation. In neurological disease models of epilepsy and stroke, reactive astrocytes upregulate P2Y1R and increase IGFBP2. The present findings identify a mechanism underlying astrocyte-driven neuronal hyperexcitability, which is likely to be shared by several neurological disorders, providing insights that might be relevant for intervention in diverse neurological disorders.

Suggested Citation

  • Eiji Shigetomi & Hideaki Suzuki & Yukiho J. Hirayama & Fumikazu Sano & Yuki Nagai & Kohei Yoshihara & Keisuke Koga & Toru Tateoka & Hideyuki Yoshioka & Youichi Shinozaki & Hiroyuki Kinouchi & Kenji F., 2024. "Disease-relevant upregulation of P2Y1 receptor in astrocytes enhances neuronal excitability via IGFBP2," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50190-7
    DOI: 10.1038/s41467-024-50190-7
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    References listed on IDEAS

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