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) 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) hippocampus, which exhibit exaggerated mGlu-induced long-term synaptic depression (LTD). In these neurons, we find that the Chrm4 transcript encoding muscarinic acetylcholine receptor 4 (M) is excessively translated, and synthesis of M downstream of mGlu activation is mimicked and occluded. Surprisingly, enhancement rather than inhibition of M activity normalizes core phenotypes in the Fmr1, including excessive protein synthesis, exaggerated mGluR-LTD, and audiogenic seizures. These results suggest that not all excessively translated mRNAs in the Fmr1 brain are detrimental, and some may be candidates for enhancement to correct pathological changes in the FX brain.