TY - JOUR
T1 - Translational control of mGluR-dependent long-term depression and object-place learning by eIF2α
AU - Di Prisco, Gonzalo Viana
AU - Huang, Wei
AU - Buffington, Shelly A.
AU - Hsu, Chih Chun
AU - Bonnen, Penelope E.
AU - Placzek, Andon N.
AU - Sidrauski, Carmela
AU - Krnjević, Krešimir
AU - Kaufman, Randal J.
AU - Walter, Peter
AU - Costa-Mattioli, Mauro
N1 - Funding Information:
We thank K. Nakazawa and L. Van Aelst for the fPKR frozen embryos and Ophn1 shRNA, respectively. This work was supported by grants from the US National Institutes of Health to M.C.-M. (NIMH 096816, NINDS 076708) and R.J.K. (DK042394, DK088227, HL052173), the Intellectual Disability Research Center (P30HD024064) and Dan L. Duncan Cancer Center (P30CA125123) Genomic and RNA Profiling Cores, and the Cancer Prevention and Research Institute of Texas (CPRIT) RP100861.
PY - 2014/8
Y1 - 2014/8
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84905106868
UR - https://www.scopus.com/pages/publications/84905106868#tab=citedBy
U2 - 10.1038/nn.3754
DO - 10.1038/nn.3754
M3 - Article
C2 - 24974795
AN - SCOPUS:84905106868
SN - 1097-6256
VL - 17
SP - 1073
EP - 1082
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 8
ER -