Abnormal AMPAR-mediated synaptic plasticity, cognitive and autistic-like behaviors in a missense Fmr1 mutant mouse model of Fragile X syndrome
Marta Prieto, et al.
Received Date: 6th April 20
Marta Prieto, Alessandra Folci, Gwénola Poupon, Sara Schiavi, Valeria Buzzelli, Urielle François, Paula Pousinha, Norma Lattuada, Sophie Abelanet, Marie Pronot, Sara Castagnola, Magda Chafai, Anouar Khayachi, Frédéric Brau, Emmanuel Deval, Maura Francolini, Barbara Bardoni, Yann Humeau, Viviana Trezza, Stéphane Martin
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.
Read in full at bioRxiv.
This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.