IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-47681-y.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-47681-y
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-47681-y?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. 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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Soo Hyun Yang & Esther Yang & Jaekwang Lee & Jin Yong Kim & Hyeijung Yoo & Hyung Sun Park & Jin Taek Jung & Dongmin Lee & Sungkun Chun & Yong Sang Jo & Gyeong Hee Pyeon & Jae-Yong Park & Hyun Woo Lee , 2023. "Neural mechanism of acute stress regulation by trace aminergic signalling in the lateral habenula in male mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Andrew Jo & Sercan Deniz & Jian Xu & Robert M. Duvoisin & Steven H. DeVries & Yongling Zhu, 2023. "A sign-inverted receptive field of inhibitory interneurons provides a pathway for ON-OFF interactions in the retina," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Shannon Trombley & Jackson Powell & Pavithran Guttipatti & Andrew Matamoros & Xiaohui Lin & Tristan O’Harrow & Tobias Steinschaden & Leann Miles & Qin Wang & Shuchao Wang & Jingyun Qiu & Qingyang Li &, 2023. "Glia instruct axon regeneration via a ternary modulation of neuronal calcium channels in Drosophila," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. Muran Wang & Peijun Li & Zewen Li & Beatriz S. Silva & Wu Zheng & Zhenghua Xiang & Yan He & Tao Xu & Cristina Cordeiro & Lu Deng & Yuwei Dai & Mengqian Ye & Zhiqing Lin & Jianhong Zhou & Xuzhao Zhou &, 2023. "Lateral septum adenosine A2A receptors control stress-induced depressive-like behaviors via signaling to the hypothalamus and habenula," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    5. Nicky Scheefhals & Manon Westra & Harold D. MacGillavry, 2023. "mGluR5 is transiently confined in perisynaptic nanodomains to shape synaptic function," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    6. Shan Yao & Min-Dong Xu & Ying Wang & Shen-Ting Zhao & Jin Wang & Gui-Fu Chen & Wen-Bing Chen & Jian Liu & Guo-Bin Huang & Wen-Juan Sun & Yan-Yan Zhang & Huan-Li Hou & Lei Li & Xiang-Dong Sun, 2023. "Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    7. Shun Li & Florian olde Heuvel & Rida Rehman & Oumayma Aousji & Albrecht Froehlich & Zhenghui Li & Rebecca Jark & Wanhong Zhang & Alison Conquest & Sarah Woelfle & Michael Schoen & Caitlin C. O´Meara &, 2023. "Interleukin-13 and its receptor are synaptic proteins involved in plasticity and neuroprotection," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    8. Francis Kei Masuda & Emily A. Aery Jones & Yanjun Sun & Lisa M. Giocomo, 2023. "Ketamine evoked disruption of entorhinal and hippocampal spatial maps," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47681-y. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.