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Nat Neurosci. 2014 Aug;17(8):1073-82. doi: 10.1038/nn.3754. Epub 2014 Jun 29.

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

Author information

1
1] Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA. [2] Memory and Brain Research Center, Baylor College of Medicine, Houston, Texas, USA. [3].
2
1] Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA. [2] Memory and Brain Research Center, Baylor College of Medicine, Houston, Texas, USA.
3
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
4
1] Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA. [2] Present address: Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, Georgia, USA.
5
Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California, USA.
6
Department of Physiology, McGill University, Montreal, Quebec, Canada.
7
Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.

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.

PMID:
24974795
PMCID:
PMC4340591
DOI:
10.1038/nn.3754
[Indexed for MEDLINE]
Free PMC Article
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