Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice

Neuron. 2012 Oct 18;76(2):325-37. doi: 10.1016/j.neuron.2012.07.022. Epub 2012 Oct 17.

Abstract

Fragile X syndrome (FXS) is the leading inherited cause of autism and intellectual disability. Aberrant synaptic translation has been implicated in the etiology of FXS, but most lines of research on therapeutic strategies have targeted protein synthesis indirectly, far upstream of the translation machinery. We sought to perturb p70 ribosomal S6 kinase 1 (S6K1), a key translation initiation and elongation regulator, in FXS model mice. We found that genetic reduction of S6K1 prevented elevated phosphorylation of translational control molecules, exaggerated protein synthesis, enhanced mGluR-dependent long-term depression (LTD), weight gain, and macro-orchidism in FXS model mice. In addition, S6K1 deletion prevented immature dendritic spine morphology and multiple behavioral phenotypes, including social interaction deficits, impaired novel object recognition, and behavioral inflexibility. Our results support the model that dysregulated protein synthesis is the key causal factor in FXS and that restoration of normal translation can stabilize peripheral and neurological function in FXS.

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

  • Analysis of Variance
  • Animals
  • Behavior, Animal / physiology*
  • Biophysics
  • Dendritic Spines / classification
  • Dendritic Spines / physiology
  • Disease Models, Animal
  • Electric Stimulation
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • Exploratory Behavior / physiology
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism
  • Fragile X Syndrome / genetics
  • Fragile X Syndrome / pathology*
  • Fragile X Syndrome / physiopathology*
  • Fragile X Syndrome / prevention & control*
  • Gene Expression Regulation / genetics*
  • Hippocampus / pathology
  • In Vitro Techniques
  • Interpersonal Relations
  • Long-Term Synaptic Depression / drug effects
  • Long-Term Synaptic Depression / genetics
  • Male
  • Maze Learning / physiology
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Methoxyhydroxyphenylglycol / analogs & derivatives
  • Methoxyhydroxyphenylglycol / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Activity / genetics
  • Mutation / genetics
  • Neurons / classification
  • Neurons / pathology
  • Patch-Clamp Techniques
  • Phenotype
  • Phosphorylation / genetics
  • Recognition, Psychology / physiology
  • Ribosomal Protein S6 Kinases, 70-kDa / deficiency*
  • Ribosomal Protein S6 Kinases, 70-kDa / genetics
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Rotarod Performance Test
  • Synapses / drug effects
  • Synapses / genetics*
  • TOR Serine-Threonine Kinases / genetics

Substances

  • Fmr1 protein, mouse
  • Fragile X Mental Retardation Protein
  • Methoxyhydroxyphenylglycol
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Extracellular Signal-Regulated MAP Kinases
  • 3,4-dihydroxyphenylglycol