Translational control of mGluR-dependent long-term depression and object-place learning by eIF2[alpha]

• Published in: Nature neuroscience Vol. 17; no. 8; p. 1073
• Main Authors: Di Prisco, Gonzalo Viana, Huang, Wei, Buffington, Shelly A, Hsu, Chih-chun, Bonnen, Penelope E, Placzek, Andon N, Sidrauski, Carmela, Krnjevic, Kresimir, Kaufman, Randal J, Walter, Peter, Costa-mattioli, Mauro
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group 01.08.2014
• Subjects: Alzheimer's disease; Information storage; Kinases; Medicine; Neurosciences; Phosphorylation; Protein synthesis; Proteins; San Francisco California; United States > US; Texas; California
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.3754

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.