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

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. Tanaka, Haruhiko Bito, Makoto Tsuda and Schuichi Koizumi ()
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Eiji Shigetomi: University of Yamanashi
Hideaki Suzuki: University of Yamanashi
Yukiho J. Hirayama: University of Yamanashi
Fumikazu Sano: University of Yamanashi
Yuki Nagai: University of Yamanashi
Kohei Yoshihara: Kyushu University
Keisuke Koga: Kyushu University
Toru Tateoka: University of Yamanashi
Hideyuki Yoshioka: University of Yamanashi
Youichi Shinozaki: 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
Schuichi Koizumi: University of Yamanashi

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50190-7

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