Mutations causing syndromic autism define an axis of synaptic pathophysiology

Nature. 2011 Nov 23;480(7375):63-8. doi: 10.1038/nature10658.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Autistic Disorder / genetics*
  • Autistic Disorder / physiopathology*
  • Disease Models, Animal
  • Electrical Synapses / pathology*
  • Female
  • Fragile X Mental Retardation Protein / genetics
  • Gene Expression Regulation
  • Hippocampus / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation*
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / metabolism
  • Syndrome
  • TOR Serine-Threonine Kinases / metabolism
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / genetics

Substances

  • Fmr1 protein, mouse
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • Tsc2 protein, mouse
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Fragile X Mental Retardation Protein
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse