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Abstract / Description of output
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.
Original language | English |
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Pages (from-to) | 550-563.e5 |
Number of pages | 19 |
Journal | Neuron |
Volume | 95 |
Issue number | 3 |
Early online date | 2 Aug 2017 |
DOIs | |
Publication status | Published - 2 Aug 2017 |
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Dive into the research topics of 'Cell-type-specific translation profiling reveals a novel strategy for treating fragile X syndrome'. Together they form a unique fingerprint.Projects
- 2 Finished
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Emily Osterweil
- Centre for Discovery Brain Sciences
- Edinburgh Neuroscience
- Deanery of Biomedical Sciences - UoE Honorary staff
Person: Academic: Research Active , Affiliated Independent Researcher