Projects per year
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.
|Number of pages||19|
|Early online date||2 Aug 2017|
|Publication status||Published - 2 Aug 2017|
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- 2 Finished
Targeting ERK and mTOR for the treatment of fragile X syndrome
1/12/14 → 31/12/18
- Deanery of Biomedical Sciences - Personal Chair of Molecular Neuroscience
- Centre for Discovery Brain Sciences
- Edinburgh Neuroscience
Person: Academic: Research Active