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Tuberous sclerosis complex and fragile X syndrome are genetic diseases characterized by intellectual disability and autism. Because both syndromes are caused by mutations in genes that regulate protein synthesis in neurons, it has been hypothesized that excessive protein synthesis is one core pathophysiological mechanism of intellectual disability and autism. Using electrophysiological and biochemical assays of neuronal protein synthesis in the hippocampus of Tsc2^sup +/-^ and Fmr1^sup -/y^ mice, here we show that synaptic dysfunction caused by these mutations actually falls at opposite ends of a physiological spectrum. Synaptic, biochemical and cognitive defects in these mutants are corrected by treatments that modulate metabotropic glutamate receptor 5 in opposite directions, and deficits in the mutants disappear when the mice are bred to carry both mutations. Thus, normal synaptic plasticity and cognition occur within an optimal range of metabotropic glutamate-receptor-mediated protein synthesis, and deviations in either direction can lead to shared behavioural impairments.
More than 1% of the human population has an autism spectrum disorder (ASD), and it has been estimated that over 50% of those with autism also have intellectual disability1. In most cases, the cause is unknown. However, genetically defined syndromes with increased prevalence of autism and intellectual disability offer an opportunity to understand the brain pathophysiology thatmanifests as ASD and intellectual disability, and this knowledge can suggest potential therapies. A case in point is fragile X syndrome (FXS), caused by silencing of the FMR1 gene and loss of the protein product, FMRP. Studies of the Fmr1 knockout (2/y) mouse revealed that in the absence of FMRP, protein synthesis is increased downstreamofmetabotropic glutamate receptor 5 (mGluR5). Diverse mutant phenotypes in fragile X animal models have been corrected by genetic or pharmacological inhibition of mGluR5, and preliminary human clinical trials using drugs that inhibit mGluR5 have shown promise2. Because several other syndromic forms of ASD and intellectual disability are associated with mutations of genes that regulate messenger RNA (mRNA) translation at synapses, it has been hypothesized that altered synaptic protein synthesis might contribute generally to the autistic phenotype, including intellectual disability3. The aim of the current study was to test the hypothesis that a mutation responsible for another genetic syndrome associated with ASD and intellectual disability-tuberous sclerosis complex (TSC)-produces abnormalities in synaptic protein synthesis and plasticity...