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

• Published in: Nature communications Vol. 15; no. 1; p. 3583
• Main Authors: Bataveljic, Danijela, Pivonkova, Helena, de Concini, Vidian, Hébert, Betty, Ezan, Pascal, Briault, Sylvain, Bemelmans, Alexis-Pierre, Pichon, Jacques, Menuet, Arnaud, Rouach, Nathalie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27-04-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/44; 14; 14/19; 14/32; 38; 631/378/1689/2608; 631/378/2596/1308; 64/110; 9/30; 9/74; Animals; Astrocytes; Astrocytes - metabolism; Behavior, Animal; Binding; Channels; Cognitive ability; Defects; Disease Models, Animal; Excitability; FMR1 protein; Fragile X Mental Retardation Protein - genetics; Fragile X Mental Retardation Protein - metabolism; Fragile X syndrome; Fragile X Syndrome - genetics; Fragile X Syndrome - metabolism; Fragile X Syndrome - physiopathology; Hippocampus; Hippocampus - metabolism; Homeostasis; Humanities and Social Sciences; Intellectual disabilities; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; mRNA; multidisciplinary; Neurodevelopmental disorders; Neurons - metabolism; Potassium; Potassium - metabolism; Potassium channels (inwardly-rectifying); Potassium Channels, Inwardly Rectifying - genetics; Potassium Channels, Inwardly Rectifying - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-47681-y

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.
Fragile X syndrome is a neurodevelopmental disorder with altered neuronal excitability and behavior. Here, the authors show that dysfunction of astroglial Kir4.1 potassium channels drives neuronal and behavioral impairments in a fragile X mouse model.