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

Di Prisco G, Huang W, Buffington S, Hsu C, Bonnen P, Placzek A, Sidrauski C, Krnjević K, Kaufman R, Walter P, Costa-Mattioli M. Translational control of mGluR-dependent long-term depression and object-place learning by eIF2α. Nat Neurosci 17:1073-82, 2014
(PMCID : PMC4340591) (PMID : 24974795) (PDF)

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.


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