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

Danijela Bataveljic, Helena Pivonkova, Vidian de Concini, Betty Hébert, Pascal Ezan, Sylvain Briault, Alexis-Pierre Bemelmans, Jacques Pichon, Arnaud Menuet and Nathalie Rouach ()
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Danijela Bataveljic: Collège de France, CNRS, INSERM, Labex Memolife, Université PSL
Helena Pivonkova: Collège de France, CNRS, INSERM, Labex Memolife, Université PSL
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
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

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47681-y

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