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 best-described monogenic cause autism. CGG-repeat expansion in FMR1 gene leads to silencing, loss-of-expression Mental Retardation Protein (FMRP), a common FXS. Missense mutations were also identified FXS patients, including recurrent FMRP-R138Q mutation. To investigate mechanisms underlying caused by this mutation, we generated knock-in mouse model ( Fmr1 R138Q ) expressing protein. We demonstrate that, hippocampus mice, neurons show an increased spine density associated with synaptic ultrastructural defects AMPA receptor-surface expression. Combining biochemical assays, high-resolution imaging, electrophysiological recordings, behavioural testing, that mutation results impaired hippocampal long-term potentiation socio-cognitive deficits mice. These findings reveal functional impact