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

Summary 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.
Highlights • TRAP-seq reveals altered translation of >120 mRNAs in Fmr1−/y CA1 pyramidal neurons • Muscarinic receptor M4 is excessively translated in Fmr1−/y hippocampus • Enhancement, not inhibition, of M4 corrects core phenotypes in the Fmr1−/y mouse • Not all excessively translating mRNAs are detrimental to Fmr1−/y brain function
Thomson et al. use TRAP-seq to identify excessive translation of muscarinic receptor M4 in Fmr1−/y neurons. Surprisingly, enhancement rather than inhibition of M4 corrects neurological Fmr1−/y phenotypes. This suggests that elevated translation of certain mRNAs in the FX brain may be protective rather than pathological.