Translational control of mGluR-dependent long-term depression and object-place learning by eIF2α

Gonzalo Viana Di Prisco, Wei Huang, Shelly A. Buffington, Chih Chun Hsu, Penelope E. Bonnen, Andon N. Placzek, Carmela Sidrauski, Krešimir Krnjević, Randal J. Kaufman, Peter Walter, Mauro Costa-Mattioli

Research output: Contribution to journalArticle

99 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1073-1082
Number of pages10
JournalNature Neuroscience
Volume17
Issue number8
DOIs
StatePublished - Aug 2014

ASJC Scopus subject areas

  • Neuroscience(all)

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    Di Prisco, G. V., Huang, W., Buffington, S. A., Hsu, C. C., Bonnen, P. E., Placzek, A. N., Sidrauski, C., Krnjević, K., Kaufman, R. J., Walter, P., & Costa-Mattioli, M. (2014). Translational control of mGluR-dependent long-term depression and object-place learning by eIF2α. Nature Neuroscience, 17(8), 1073-1082. https://doi.org/10.1038/nn.3754