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.National Institute of Mental Health (U.S.) (T32 MH-082718)National Institute of Mental Health (U.S.) (T32-MH-074249)Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (2R01HD046943)United States. Dept. of Defense (W81XWH-11-1-0252)Simons Foundatio

Lifting the Mood on Treating Fragile X

Only a decade ago, it was believed that a genetic diagnosis of intellectual disability and autism offered little in the way of hope for a medical treatment to lessen the burden on the affected individuals and their families. However, recent research aimed at understanding the cellular and molecular mechanisms that underlie the pathogenesis of ASD has ushered in a new era of targeted treatment strategies. Studies in fragile X syndrome (FXS) have been at the forefront of this revolution, and they are forging a path that could define future approaches to the treatment of ASD

A role for myosin VI in postsynaptic structure and glutamate receptor endocytosis

Myosin VI (Myo6) is an actin-based motor protein implicated in clathrin-mediated endocytosis in nonneuronal cells, though little is known about its function in the nervous system. Here, we find that Myo6 is highly expressed throughout the brain, localized to synapses, and enriched at the postsynaptic density. Myo6-deficient (Snell's waltzer; sv/sv) hippocampus exhibits a decrease in synapse number, abnormally short dendritic spines, and profound astrogliosis. Similarly, cultured sv/sv hippocampal neurons display decreased numbers of synapses and dendritic spines, and dominant-negative disruption of Myo6 in wild-type hippocampal neurons induces synapse loss. Importantly, we find that sv/sv hippocampal neurons display a significant deficit in the stimulation-induced internalization of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid–type glutamate receptors (AMPARs), and that Myo6 exists in a complex with the AMPAR, AP-2, and SAP97 in brain. These results suggest that Myo6 plays a role in the clathrin-mediated endocytosis of AMPARs, and that its loss leads to alterations in synaptic structure and astrogliosis