title: Mutations causing syndromic autism define an axis of synaptic pathophysiology.
abstract: 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.
authors: Howard Hughes Medical Institute, The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors: Benjamin D
authors: BD
authors: Auerbach
authors: Emily K
authors: EK
authors: Osterweil
authors: Mark F
authors: MF
authors: Bear
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000503:physiopathology*; D004195:Disease Models, Animal; D054351:Electrical Synapses / Q000473:pathology*; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D013577:Syndrome; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C497684:Fmr1 protein, mouse; C000624654:Tsc2 protein, mouse; C546843:mTOR protein, mouse