Translational control of mGluR-dependent long-term depression and object-place learning by eIF2α.
Nat Neurosci
; 17(8): 1073-82, 2014 Aug.
Article
em En
| MEDLINE
| ID: mdl-24974795
ABSTRACT
At hippocampal synapses, activation of group I metabotropic glutamate receptors (mGluRs) induces long-term depression (LTD), which requires new protein synthesis. However, the underlying mechanism remains elusive. Here we describe the translational program that underlies mGluR-LTD and identify the translation factor eIF2α as its master effector. Genetically reducing eIF2α phosphorylation, or specifically blocking the translation controlled by eIF2α phosphorylation, prevented mGluR-LTD and the internalization of surface AMPA receptors (AMPARs). Conversely, direct phosphorylation of eIF2α, bypassing mGluR activation, triggered a sustained LTD and removal of surface AMPARs. Combining polysome profiling and RNA sequencing, we identified the mRNAs translationally upregulated during mGluR-LTD. Translation of one of these mRNAs, oligophrenin-1, mediates the LTD induced by eIF2α phosphorylation. Mice deficient in phospho-eIF2α-mediated translation are impaired in object-place learning, a behavioral task that induces hippocampal mGluR-LTD in vivo. Our findings identify a new model of mGluR-LTD, which promises to be of value in the treatment of mGluR-LTD-linked cognitive disorders.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Biossíntese de Proteínas
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Fator de Iniciação 2 em Eucariotos
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Receptores de Glutamato Metabotrópico
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Receptores de AMPA
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Depressão Sináptica de Longo Prazo
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Aprendizagem
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article