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Cited by 40Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchIon channel regulation and function

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

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Bataveljic, Danijela, Pivonkova, Helena, de Concini, Vidian, Hébert, Betty, Ezan, Pascal, Briault, Sylvain, Bemelmans, Alexis-Pierre, Pichon, Jacques +2 more·2024·Nature Communications
DOI 10.1038/s41467-024-47681-yPMC PMC11055954
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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.

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  • Astrocytes in FMR1 knockout mice show reduced branch complexity and altered calcium signaling, which can disturb glutamate uptake and neuromodulator handling, thereby amplifying excitatory drive.

    “Astrocytes in FMR1 knockout mice show reduced branch complexity and altered calcium signaling, which can disturb glutamate uptake and neuromodulator handling, thereby amplifying excitatory drive (Bataveljic et al., 2024).”

    From Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder (2026) · cites this paper as Bataveljic et al., 2024

    The Results section (‘Decreased Kir4.1 expression in Fmr1 KO astrocytes’; page not provided) says astrocyte morphology was unchanged in Fmr1 KO hippocampus, contrary to the claimed reduced branch complexity. The Discussion attributes neuronal hyperexcitability to impaired Kir4.1-mediated potassium clearance, not to the proposed calcium-signaling, glutamate-uptake, or neuromodulator-handling pathway. (LLM, conf=0.88)

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  • FMR1 knockout mice show hypersynchronous population activity, larger and more stable neuronal assemblies, and a shift toward excessive excitation in hippocampal networks.

    “FMR1 knockout mice show hypersynchronous population activity, larger and more stable neuronal assemblies, and a shift toward excessive excitation in hippocampal networks (Bataveljic et al., 2024).”

    From Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder (2026) · cites this paper as Bataveljic et al., 2024

    The Results section ('Increased neuronal excitability and extracellular potassium levels in FMRP-deficient mice'; page unavailable) reports greater excitability of hippocampal CA1 neurons in Fmr1 knockout mice. It does not report hypersynchronous population activity, larger or more stable neuronal assemblies, or a measured shift in the network excitation–inhibition balance. (LLM, conf=0.86)

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Authors
Bataveljic, D., Pivonkova, H., de Concini, V., Hébert, B., Ezan, P., Briault, S., Bemelmans, A.-P., Pichon, J., Menuet, A., & Rouach, N.
Affiliations
  • Université d'Orléans (FR)
  • Centre National de la Recherche Scientifique (FR)
  • Université Paris-Sud (FR)
Corresponding author
Rouach, Nathalie
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-04-27
Volume
15
Issue
1
Pages
3583-3583
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-47681-y
PMC
PMC11055954
OpenAlex
W4395690386
Cited by
40
References
7
Citations by year
2026: 19 · 2025: 18 · 2024: 3
FWCI
10.62
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • FRAXA Research Foundation
  • Infrastructures en Biologie Santé et Agronomie
  • European Commission (HORIZON2020, 722053)
  • Fondation Jérôme Lejeune
  • Centre National de la Recherche Scientifique
  • Université d'Orléans
  • H2020 European Research Council (683154)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Keywords
fragile X syndrome, Kir4.1 potassium channel, astrocytes, FMRP, neuronal hyperexcitability, hippocampus, social behavior, cognitive impairment, Fmr1 knockout mice, viral gene delivery, therapeutic target
MeSH terms
Kcnj10 Channel, Animals, Astrocytes, Behavior, Animal, Disease Models, Animal, Fragile X Syndrome, Hippocampus, Male, Mice, Inbred C57BL, Neurons, Potassium, RNA, Messenger, Mice, Knockout, Potassium Channels, Inwardly Rectifying, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1

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