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Astroglial Kir4.1 potassium channel deficit drives neuronal hyperexcitability and behavioral defects in Fragile X syndrome mouse model
D. Bataveljic, H. Pivonkova, V. de Concini, B. Hébert, P. Ezan, S. Briault, AP. Bemelmans, J. Pichon, A. Menuet, N. Rouach
Language English Country England, Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural
Grant support
683154
EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013))
722053
EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
1535
Fondation Jérôme Lejeune (Jérôme Lejeune Foundation)
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- MeSH
- Astrocytes * metabolism MeSH
- Behavior, Animal MeSH
- Potassium metabolism MeSH
- Potassium Channels, Inwardly Rectifying * metabolism genetics MeSH
- Hippocampus metabolism MeSH
- RNA, Messenger metabolism genetics MeSH
- Disease Models, Animal MeSH
- Mice, Inbred C57BL MeSH
- Mice, Knockout MeSH
- Mice MeSH
- Neurons * metabolism physiology MeSH
- Fragile X Mental Retardation Protein * metabolism genetics MeSH
- Fragile X Syndrome * metabolism genetics physiopathology MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
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.
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
References provided by Crossref.org
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