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.

Commissariat à l'Energie Atomique et aux Energies Alternatives Département de la Recherche Fondamentale Institut de biologie François Jacob MIRCen and CNRS UMR 9199 Université Paris Sud Neurodegenerative Diseases Laboratory Fontenay aux Roses 92260 France

Department of Biomedical Sciences University of Antwerp Antwerp Belgium

Department of Genetics Regional Hospital Orléans France

Department of Physiology 2nd Faculty of Medicine Charles University Prague Czech Republic

Experimental and Molecular Immunology and Neurogenetics CNRS UMR7355 and Orléans University Orléans France

Neuroglial Interactions in Cerebral Physiology and Pathologies Center for Interdisciplinary Research in Biology Collège de France CNRS INSERM Labex Memolife Université PSL Paris France

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