Abnormal AMPAR-mediated synaptic plasticity, cognitive and autistic-like behaviors in a missenseFmr1mutant mouse model of Fragile X syndrome

Abstract

Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and the bestdescribed 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 (Fmr1 R138Q ) expressing the FMRP-R138Q protein. We demonstrate that the Fmr1 R138Q hippocampus has an increased spine density associated with postsynaptic ultrastructural defects and increased AMPA receptor surface expression. Combining biochemical assays, highresolution imaging and electrophysiological recordings, we also show that the mutation impairs the hippocampal long-term potentiation (LTP) and leads to socio-cognitive deficits in Fmr1 R138Q mice.These findings reveal that the R138Q mutation impacts the postsynaptic function of FMRP and highlight potential mechanisms causing FXS in FMRP-R138Q patients. IntroductionThe formation of functional synapses in the developing brain is fundamental to establishing efficient neuronal communication and plasticity, which underlie cognitive processes. In the past years, synaptic dysfunction has clearly emerged as a critical factor in the aetiology of neurodevelopmental disorders including Autism Spectrum disorder (ASD) and Intellectual Disability (ID). X-linked ID (XLID) accounts for 5-10% of ID patients and is caused by mutations in genes located on the X chromosome.The Fragile X Syndrome (FXS) is the most frequent form of inherited XLID and the first monogenic cause of ASD with a prevalence of 1:4000 males and 1:7000 females 1 . The majority of FXS patients exhibit mild-to-severe ID associated with significant learning and memory impairments, Attention Deficit Hyperactivity Disorder (ADHD) and autistic-like features 2-4 . To date, no effective therapeutic strategies are available.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 consequently, the lack of expression of the encoded Fragile X Mental Retardation Protein (FMRP) 2,5 . FMRP is an RNA-binding protein that binds a large subset of mRNAs in the mammalian brain and is a key component of RNA granules. These granules transport translationally-repressed mRNAs essential for the synaptic function along axons and dendrites 1,3 . Neuronal activation triggers the local translation of these critical mRNAs at synapses allowing spine maturation and elimination, which are essential processes to shape a functional neuronal network in the developing brain. Accordingly, the lack of FMRP expression in FXS patients and Fmr1 knockout (Fmr1-KO) animal models leads to a pathological increase in immature dendritic protrusions due to a failure in the synapse maturation and/or elimination processes 6 . These defects co...