Cell-Type-Specific Translation Profiling Reveals a Novel Strategy for Treating Fragile X Syndrome

Neuron. 2017 Aug 2;95(3):550-563.e5. doi: 10.1016/j.neuron.2017.07.013.


Excessive mRNA translation downstream of group I metabotropic glutamate receptors (mGlu1/5) is a core pathophysiology of fragile X syndrome (FX); however, the differentially translating mRNAs that contribute to altered neural function are not known. We used translating ribosome affinity purification (TRAP) and RNA-seq to identify mistranslating mRNAs in CA1 pyramidal neurons of the FX mouse model (Fmr1-/y) hippocampus, which exhibit exaggerated mGlu1/5-induced long-term synaptic depression (LTD). In these neurons, we find that the Chrm4 transcript encoding muscarinic acetylcholine receptor 4 (M4) is excessively translated, and synthesis of M4 downstream of mGlu5 activation is mimicked and occluded. Surprisingly, enhancement rather than inhibition of M4 activity normalizes core phenotypes in the Fmr1-/y, including excessive protein synthesis, exaggerated mGluR-LTD, and audiogenic seizures. These results suggest that not all excessively translated mRNAs in the Fmr1-/y brain are detrimental, and some may be candidates for enhancement to correct pathological changes in the FX brain.

Keywords: FMR1; FMRP; LTD; TRAP; autism; fragile X; m4; mglur theory; muscarinic receptor; protein synthesis.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism*
  • Fragile X Syndrome / drug therapy*
  • Fragile X Syndrome / genetics
  • Fragile X Syndrome / metabolism
  • Hippocampus / cytology*
  • Long-Term Synaptic Depression / physiology*
  • Methoxyhydroxyphenylglycol / pharmacology
  • Mice, Transgenic
  • Neurons / cytology*
  • Protein Biosynthesis / drug effects
  • Receptors, Metabotropic Glutamate / metabolism


  • Receptors, Metabotropic Glutamate
  • Fragile X Mental Retardation Protein
  • Methoxyhydroxyphenylglycol