Cell-Type-Specific Translation Profiling Reveals a Novel Strategy for Treating Fragile X Syndrome.
Neuron
; 95(3): 550-563.e5, 2017 Aug 02.
Article
em En
| MEDLINE
| ID: mdl-28772121
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Depressão Sináptica de Longo Prazo
/
Proteína do X Frágil da Deficiência Intelectual
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Síndrome do Cromossomo X Frágil
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Hipocampo
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Neurônios
Limite:
Animals
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article