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

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.
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https://www.hal.inserm.fr/inserm-03172160
Contributor : Stephane Martin <>
Submitted on : Wednesday, March 17, 2021 - 3:11:53 PM
Last modification on : Tuesday, June 29, 2021 - 3:34:36 AM

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Marta Prieto, Alessandra Folci, Gwénola Poupon, Sara Schiavi, Valeria Buzzelli, et al.. Missense mutation of Fmr1 results in impaired AMPAR-mediated plasticity and socio-cognitive deficits in mice. Nature Communications, Nature Publishing Group, 2021, 12 (1), pp.1557. ⟨10.1038/s41467-021-21820-1⟩. ⟨inserm-03172160⟩

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