Cell-Type-Specific Translation Profiling Reveals a Novel Strategy for Treating Fragile X Syndrome
Year: 2017
Type: article
Abstract: 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 (M 4 ) is excessively translated, and synthesis of M 4 downstream of mGlu 5 activation is mimicked and occluded. Surprisingly, enhancement rather than inhibition of M 4 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.
Source: Neuron
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,006
Awards: The neuropathophysiology associated with Syngap mutations: further evidence for an mGluR5 signaling axis in ID/ASD, Differential regulation of protein synthesis in synaptic plasticity and autism spectrum disorders with associated intellectual disability (ASD/ID)., Targeting ERK and mTOR for the treatment of fragile X syndrome, MICA: Correction of behavioural, circuit and cellular deficits in rat models of ID/ASD
OpenAlex ID: W2744596343