Cell type-specific translation profiling reveals a novel strategy for treating fragile X syndrome

Sophie R. Thomson*1,2, Sang S. Seo*1,2, Stephanie A. Barnes✝1,2, Susana R. Louros✝1,2, Melania Muscas1,2, Owen Dando1,2, Caomihe Kirby1,2, David J.A. Wyllie1,2, Giles E. Hardingham1,2,3, Peter C. Kind1,2, and Emily K. Osterweil1,2

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 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.