Exploring the molecular and morpho-functional differences in a knock-in model of Fragile X syndrome

Fragile X syndrome (FXS) is the most common inherited form of Intellectual Disability and a leading monogenic cause of autism. FXS results from mutations within the FMR1 gene causing the loss-of-function of the RNA-binding Fragile X Messenger RibonucleoProtein (FMRP). FMRP transports mRNAs along dendrites toward the base of active synapses for their activity-dependent translation. In FXS, the loss-of-function of FMRP leads to a hyper-abundance of dendritic protrusions. Several FMR1 missense mutations identified in patients also lead FXS but how these mutations affect the function of FMRP and lead to the disease, remain largely unknown. Thus, we successfully engineered a Knock-in mouse model expressing the recurrent R138Q mutation FXS mutation (KI-R138Q). We published that these mice show critical synaptic defects with an increased spine density as well as alterations in the surface levels of AMPA receptors in the hippocampus leading to synaptic plasticity defects and to impaired socio-cognitive behaviors. Here we used this unique FXS model and a combination of state-of-the-art approaches to examine further the alterations caused by the FXS mutation. We report a differential post-natal expression of metabotropic glutamate receptors (mGluR) in the KI brain, immunohistochemical differences and alterations in local mGluR-dependent translation in dendrites using puromycilation assays. We also highlight significant differences in the metabolic activity of various brain areas using PET imaging with specific allosteric modulators of glutamate receptors. Overall, our work provides additional evidence regarding the detrimental effects of the FXS missense mutation which is important prior to envisage the development of any preclinical tests.