Abnormal AMPAR-mediated synaptic plasticity, cognitive and autistic-like behaviors in a missense Fmr1 mutant mouse model of Fragile X syndrome

Prieto, M.; Folci, A.; Poupon, G.; Schiavi, S.; Buzzelli, V.; Francois, U.; Pousinha, P.; Lattuada, N.; Abelanet, S.; Pronot, M.; Castagnola, S.; Chafai, M.; Khayachi, A.; Brau, F.; Deval, E.; Francolini, M.; Bardoni, B.; Humeau, Y.; Trezza, V.; Martin, S.

doi:10.1101/2020.04.19.048819

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bioRxiv · 10.1101/2020.04.19.048819

Abnormal AMPAR-mediated synaptic plasticity, cognitive and autistic-like behaviors in a missense Fmr1 mutant mouse model of Fragile X syndrome

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Abstract

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 synaptic functions of FMRP and highlight potential mechanisms causing FXS in FMRP-R138Q patients.

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Prieto, M., Folci, A., Poupon, G., Schiavi, S., Buzzelli, V., Francois, U., Pousinha, P., Lattuada, N., Abelanet, S., Pronot, M., Castagnola, S., Chafai, M., Khayachi, A., Brau, F., Deval, E., Francolini, M., Bardoni, B., Humeau, Y., Trezza, V., Martin, S.. 2020-04-19. Abnormal AMPAR-mediated synaptic plasticity, cognitive and autistic-like behaviors in a missense Fmr1 mutant mouse model of Fragile X syndrome. https://doi.org/10.1101/2020.04.19.048819

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