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Astroglial Kir4.1 potassium channel deficit drives neuronal hyperexcitability and behavioral defects in Fragile X syndrome mouse model

Author

Listed:
  • Danijela Bataveljic

    (Collège de France, CNRS, INSERM, Labex Memolife, Université PSL
    University of Antwerp)

  • Helena Pivonkova

    (Collège de France, CNRS, INSERM, Labex Memolife, Université PSL
    Charles University)

  • Vidian de Concini

    (CNRS UMR7355 and Orléans University)

  • Betty Hébert

    (CNRS UMR7355 and Orléans University)

  • Pascal Ezan

    (Collège de France, CNRS, INSERM, Labex Memolife, Université PSL)

  • Sylvain Briault

    (CNRS UMR7355 and Orléans University
    Regional Hospital)

  • Alexis-Pierre Bemelmans

    (Université Paris-Sud, Neurodegenerative Diseases Laboratory)

  • Jacques Pichon

    (CNRS UMR7355 and Orléans University)

  • Arnaud Menuet

    (CNRS UMR7355 and Orléans University)

  • Nathalie Rouach

    (Collège de France, CNRS, INSERM, Labex Memolife, Université PSL)

Abstract

Fragile X syndrome (FXS) is an inherited form of intellectual disability caused by the loss of the mRNA-binding fragile X mental retardation protein (FMRP). FXS is characterized by neuronal hyperexcitability and behavioral defects, however the mechanisms underlying these critical dysfunctions remain unclear. Here, using male Fmr1 knockout mouse model of FXS, we identify abnormal extracellular potassium homeostasis, along with impaired potassium channel Kir4.1 expression and function in astrocytes. Further, we reveal that Kir4.1 mRNA is a binding target of FMRP. Finally, we show that the deficit in astroglial Kir4.1 underlies neuronal hyperexcitability and several behavioral defects in Fmr1 knockout mice. Viral delivery of Kir4.1 channels specifically to hippocampal astrocytes from Fmr1 knockout mice indeed rescues normal astrocyte potassium uptake, neuronal excitability, and cognitive and social performance. Our findings uncover an important role for astrocyte dysfunction in the pathophysiology of FXS, and identify Kir4.1 channel as a potential therapeutic target for FXS.

Suggested Citation

  • Danijela Bataveljic & Helena Pivonkova & Vidian de Concini & Betty Hébert & Pascal Ezan & Sylvain Briault & Alexis-Pierre Bemelmans & Jacques Pichon & Arnaud Menuet & Nathalie Rouach, 2024. "Astroglial Kir4.1 potassium channel deficit drives neuronal hyperexcitability and behavioral defects in Fragile X syndrome mouse model," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47681-y
    DOI: 10.1038/s41467-024-47681-y
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    References listed on IDEAS

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    1. Elisabetta Aloisi & Katy Corf & Julien Dupuis & Pei Zhang & Melanie Ginger & Virginie Labrousse & Michela Spatuzza & Matthias Georg Haberl & Lara Costa & Ryuichi Shigemoto & Anke Tappe-Theodor & Filip, 2017. "Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
    2. Yihui Cui & Yan Yang & Zheyi Ni & Yiyan Dong & Guohong Cai & Alexandre Foncelle & Shuangshuang Ma & Kangning Sang & Siyang Tang & Yuezhou Li & Ying Shen & Hugues Berry & Shengxi Wu & Hailan Hu, 2018. "Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression," Nature, Nature, vol. 554(7692), pages 323-327, February.
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