TY - JOUR T1 - Abnormal AMPAR-mediated synaptic plasticity, cognitive and autistic-like behaviors in a missense <em>Fmr1</em> mutant mouse model of Fragile X syndrome JF - bioRxiv DO - 10.1101/2020.04.19.048819 SP - 2020.04.19.048819 AU - Marta Prieto AU - Alessandra Folci AU - Gwénola Poupon AU - Sara Schiavi AU - Valeria Buzzelli AU - Urielle François AU - Paula Pousinha AU - Norma Lattuada AU - Sophie Abelanet AU - Marie Pronot AU - Sara Castagnola AU - Magda Chafai AU - Anouar Khayachi AU - Frédéric Brau AU - Emmanuel Deval AU - Maura Francolini AU - Barbara Bardoni AU - Yann Humeau AU - Viviana Trezza AU - Stéphane Martin Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/04/19/2020.04.19.048819.abstract N2 - Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and the best-described monogenic cause of autism. FXS is usually caused by a CGG-repeat expansion in the FMR1 gene leading to its silencing and the loss-of-expression of the Fragile X Mental Retardation Protein (FMRP). Missense mutations were also identified in FXS patients, including the recurrent FMRP-R138Q mutation. To investigate the mechanisms underlying FXS in these patients, we generated a knock-in mouse model (Fmr1R138Q) expressing the FMRP-R138Q protein. We demonstrate that the Fmr1R138Q hippocampus has an increased spine density associated with postsynaptic ultrastructural defects and increased AMPA receptor surface expression. Combining biochemical assays, high-resolution imaging and electrophysiological recordings, we also show that the mutation impairs the hippocampal long-term potentiation (LTP) and leads to socio-cognitive deficits in Fmr1R138Q mice. These findings reveal that the R138Q mutation impacts the postsynaptic function of FMRP and highlight potential mechanisms causing FXS in FMRP-R138Q patients.Competing Interest StatementThe authors have declared no competing interest. ER -