Missense mutation of Fmr1 results in impaired AMPAR-mediated plasticity and socio-cognitive deficits in mice

Marta Prieto, Alessandra Folci, Gwénola Poupon, Sara Schiavi, Valeria Buzzelli, Marie Pronot, Urielle François, Paula Pousinha, Norma Lattuada, Sophie Abelanet, Sara Castagnola, Magda Chafai, Anouar Khayachi, Carole Gwizdek, Frédéric Brau, Emmanuel Deval, Maura Francolini, Barbara Bardoni, Yann Humeau, Viviana Trezza and Stéphane Martin ()
Additional contact information
Marta Prieto: Université Côte d’Azur, CNRS, IPMC
Alessandra Folci: Université Côte d’Azur, CNRS, IPMC
Gwénola Poupon: Université Côte d’Azur, CNRS, IPMC
Sara Schiavi: RomaTre University, Dept. Science
Valeria Buzzelli: RomaTre University, Dept. Science
Marie Pronot: Université Côte d’Azur, CNRS, IPMC
Urielle François: University of Bordeaux, CNRS, IINS
Paula Pousinha: Université Côte d’Azur, CNRS, IPMC
Norma Lattuada: Università degli Studi di Milano, Dept. of Medical Biotechnology and Translational Medicine
Sophie Abelanet: Université Côte d’Azur, CNRS, IPMC
Sara Castagnola: Université Côte d’Azur, CNRS, IPMC
Magda Chafai: Université Côte d’Azur, CNRS, IPMC
Anouar Khayachi: Université Côte d’Azur, CNRS, IPMC
Carole Gwizdek: Université Côte d’Azur, CNRS, IPMC
Frédéric Brau: Université Côte d’Azur, CNRS, IPMC
Emmanuel Deval: Université Côte d’Azur, CNRS, IPMC
Maura Francolini: Università degli Studi di Milano, Dept. of Medical Biotechnology and Translational Medicine
Barbara Bardoni: Université Côte d’Azur, Inserm, CNRS, IPMC
Yann Humeau: University of Bordeaux, CNRS, IINS
Viviana Trezza: RomaTre University, Dept. Science
Stéphane Martin: Université Côte d’Azur, Inserm, CNRS, IPMC

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and the best-described monogenic cause of autism. CGG-repeat expansion in the FMR1 gene leads to FMR1 silencing, loss-of-expression of the Fragile X Mental Retardation Protein (FMRP), and is a common cause of FXS. Missense mutations in the FMR1 gene were also identified in FXS patients, including the recurrent FMRP-R138Q mutation. To investigate the mechanisms underlying FXS caused by this mutation, we generated a knock-in mouse model (Fmr1R138Q) expressing the FMRP-R138Q protein. We demonstrate that, in the hippocampus of the Fmr1R138Q mice, neurons show an increased spine density associated with synaptic ultrastructural defects and increased AMPA receptor-surface expression. Combining biochemical assays, high-resolution imaging, electrophysiological recordings, and behavioural testing, we also show that the R138Q mutation results in impaired hippocampal long-term potentiation and socio-cognitive deficits in mice. These findings reveal the functional impact of the FMRP-R138Q mutation in a mouse model of FXS.

Date: 2021
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DOI: 10.1038/s41467-021-21820-1

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