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

Excessive mRNA translation downstream of group I metabotropic glutamate receptors (mGlu_1/5) 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 mGlu_1/5-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.