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.
Highlights
Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and the best-described monogenic cause of autism
FXS generally results from a massive expansion of the trinucleotide CGG (> 200 repeats) in the 5′-UTR region of the FMR1 gene leading to its transcriptional silencing and the lack of expression of the encoded Fragile X Mental Retardation Protein (FMRP)[2,5]
To assess whether the R138Q mutation affects the developmental profile of FMRP, we compared the FMRP protein levels in the brain of WT and Fmr1R138Q mice at different postnatal days (PND) (Fig. 1b)
Summary
Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and the best-described monogenic cause of autism. High-resolution imaging, electrophysiological recordings, and behavioural testing, we 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 FMRPR138Q mutation in a mouse model of FXS. FXS generally results from a massive expansion of the trinucleotide CGG (> 200 repeats) in the 5′-UTR region of the FMR1 gene leading to its transcriptional silencing and the lack of expression of the encoded Fragile X Mental Retardation Protein (FMRP)[2,5]. Mediated synaptic plasticity, including Long-Term Depression (LTD) and Potentiation (LTP)[1,7] These defects lead to learning and memory deficits and underlie the abnormal socio-emotional behaviors in Fmr1-KO mice[1,7]
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