1. Missense mutation of Fmr1 results in impaired AMPAR-mediated plasticity and socio-cognitive deficits in mice
- Author
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Gwénola Poupon, Sara Castagnola, Sara Schiavi, Marta Prieto, Alessandra Folci, Viviana Trezza, Frédéric Brau, Emmanuel Deval, Sophie Abelanet, Carole Gwizdek, Marie Pronot, Stéphane Martin, Urielle François, Anouar Khayachi, Barbara Bardoni, Yann Humeau, Paula A. Pousinha, N. Lattuada, Maura Francolini, Magda Chafai, Valeria Buzzelli, Prieto, M., Folci, A., Poupon, G., Schiavi, S., Buzzelli, V., Pronot, M., Francois, U., Pousinha, P., Lattuada, N., Abelanet, S., Castagnola, S., Chafai, M., Khayachi, A., Gwizdek, C., Brau, F., Deval, E., Francolini, M., Bardoni, B., Humeau, Y., Trezza, V., Martin, S., Martin, Stephane, Explorer des stratégies innovantes pour restaurer la fonction synaptique et les comportements sociocognitifs dans un modèle murin exprimant une mutation récurrente du syndrome du X fragile chez l'humain - - InnoVinFXS2020 - ANR-20-CE16-0006 - AAPG2020 - VALID, Idex UCA JEDI - - UCA JEDI2015 - ANR-15-IDEX-0001 - IDEX - VALID, Centres d'excellences - Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie - - SIGNALIFE2011 - ANR-11-LABX-0028 - LABX - VALID, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Università degli Studi Roma Tre = Roma Tre University (ROMA TRE), Interdisciplinary Institute for Neuroscience [Bordeaux] (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Milano = University of Milan (UNIMI), ANR-20-CE16-0006,InnoVinFXS,Explorer des stratégies innovantes pour restaurer la fonction synaptique et les comportements sociocognitifs dans un modèle murin exprimant une mutation récurrente du syndrome du X fragile chez l'humain(2020), ANR-15-IDEX-0001,UCA JEDI,Idex UCA JEDI(2015), ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Università degli Studi Roma Tre, Università degli Studi di Milano [Milano] (UNIMI), and ANR-15-IDEX-01
- Subjects
0301 basic medicine ,Male ,Patch-Clamp Techniques ,[SDV]Life Sciences [q-bio] ,Long-Term Potentiation ,General Physics and Astronomy ,Hippocampus ,Membrane trafficking ,medicine.disease_cause ,Fragile X Mental Retardation Protein ,Mice ,0302 clinical medicine ,Missense mutation ,Cells, Cultured ,Mutation ,Multidisciplinary ,Brain ,Long-term potentiation ,Autism spectrum disorders ,Fragile X syndrome ,[SDV] Life Sciences [q-bio] ,Mechanisms of disease ,Receptors, Glutamate ,Female ,congenital, hereditary, and neonatal diseases and abnormalities ,Science ,Immunoblotting ,Mutation, Missense ,AMPA receptor ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,medicine ,Animals ,Humans ,Biotinylation ,Cognitive Dysfunction ,Protein transport ,General Chemistry ,medicine.disease ,FMR1 ,nervous system diseases ,030104 developmental biology ,Autism ,Neuroscience ,030217 neurology & neurosurgery - 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., The R138Q mutation in the Fragile X Mental Retardation 1 (FMR1) gene has been associated with Fragile X syndrome (FXS). Here, the authors present a Fmr1R138Q Knock-In mouse model and show that R138Q mutation results in impaired long-term potentiation and socio-cognitive performance in these mice.
- Published
- 2021