Mutations causing syndromic autism define an axis of synaptic pathophysiology

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 +/− and Fmr1 −/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. The mutations that underlie the diseases tuberous sclerosis complex and fragile X syndrome produce abnormalities in synaptic plasticity and function that can be corrected by treatments that modulate metabotropic glutamate receptor 5 in opposite directions. Contrasting mutants linked to autism Recent studies suggest that autism spectrum disorder and associated intellectual disability may arise from altered plasticity and function of synapses in the brain. This is exemplified by a series of experiments on mice carrying the single gene defects associated with tuberous sclerosis complex and fragile X syndrome, two genetic diseases characterized by intellectual disability and autism. Both mutations are associated with altered protein synthesis in neurons, so it was expected that similar treatments would be beneficial in both. However, synaptic dysfunction and cognitive deficits caused by these mutations are corrected by treatments that modulate metabotropic glutamate receptor 5 (mGluR 5) in opposite directions, and the effects of the two mutations cancel each other when introduced simultaneously. This suggests that the two mutations can cause similar dysfunction by deviating from an optimal range of mGluR-mediated activity in opposite directions.