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Translational control of mGluR-dependent long-term depression and object-place learning by eIF2α
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Translational control of mGluR-dependent long-term depression and object-place learning by eIF2α
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Journal Article
Translational control of mGluR-dependent long-term depression and object-place learning by eIF2α
2014
Overview
The authors show that phosphorylation of the translation factor eIF2α is necessary and sufficient for mGluR-LTD. They identify mRNAs that are translated during mGluR-LTD and regulated by p-eIF2α, including
Ophn1
as a key target. Deficient p-eIF2α-mediated translation impairs object-place learning, which requires mGluR-LTD. eIF2α phosphorylation may determine whether synapses undergo LTD or LTP.
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.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 38/91
/ 82
/ 9/74
/ 96
/ 96/106
/ Animal Genetics and Genomics
/ Animals
/ Biomedical and Life Sciences
/ Eukaryotic Initiation Factor-2 - genetics
/ Eukaryotic Initiation Factor-2 - metabolism
/ Long-Term Synaptic Depression - genetics
/ Male
/ Mice
/ Receptors, AMPA - deficiency
/ Receptors, AMPA - physiology
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