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

Gonzalo Viana Di Prisco, Wei Huang, Shelly Buffington, Chih Chun Hsu, Penelope E. Bonnen, Andon N. Placzek, Carmela Sidrauski, Krešimir Krnjević, Randal J. Kaufman, Peter Walter, Mauro Costa-Mattioli

Research output: Contribution to journalArticle

85 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1073-1082
Number of pages10
JournalNature Neuroscience
Volume17
Issue number8
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

Learning
Depression
Phosphorylation
AMPA Receptors
RNA Sequence Analysis
Metabotropic Glutamate Receptors
Polyribosomes
Protein Biosynthesis
Synapses
Messenger RNA
Proteins

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Di Prisco, G. V., Huang, W., Buffington, S., Hsu, C. C., Bonnen, P. E., Placzek, A. N., ... Costa-Mattioli, M. (2014). Translational control of mGluR-dependent long-term depression and object-place learning by eIF2α. Nature Neuroscience, 17(8), 1073-1082. https://doi.org/10.1038/nn.3754

Translational control of mGluR-dependent long-term depression and object-place learning by eIF2α. / Di Prisco, Gonzalo Viana; Huang, Wei; Buffington, Shelly; Hsu, Chih Chun; Bonnen, Penelope E.; Placzek, Andon N.; Sidrauski, Carmela; Krnjević, Krešimir; Kaufman, Randal J.; Walter, Peter; Costa-Mattioli, Mauro.

In: Nature Neuroscience, Vol. 17, No. 8, 01.01.2014, p. 1073-1082.

Research output: Contribution to journalArticle

Di Prisco, GV, Huang, W, Buffington, S, Hsu, CC, Bonnen, PE, Placzek, AN, Sidrauski, C, Krnjević, K, Kaufman, RJ, Walter, P & Costa-Mattioli, M 2014, 'Translational control of mGluR-dependent long-term depression and object-place learning by eIF2α', Nature Neuroscience, vol. 17, no. 8, pp. 1073-1082. https://doi.org/10.1038/nn.3754
Di Prisco, Gonzalo Viana ; Huang, Wei ; Buffington, Shelly ; Hsu, Chih Chun ; Bonnen, Penelope E. ; Placzek, Andon N. ; Sidrauski, Carmela ; Krnjević, Krešimir ; Kaufman, Randal J. ; Walter, Peter ; Costa-Mattioli, Mauro. / Translational control of mGluR-dependent long-term depression and object-place learning by eIF2α. In: Nature Neuroscience. 2014 ; Vol. 17, No. 8. pp. 1073-1082.
@article{f27eb134b04a483c83eb82ac9b89b6b3,
title = "Translational control of mGluR-dependent long-term depression and object-place learning by eIF2α",
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.",
author = "{Di Prisco}, {Gonzalo Viana} and Wei Huang and Shelly Buffington and Hsu, {Chih Chun} and Bonnen, {Penelope E.} and Placzek, {Andon N.} and Carmela Sidrauski and Krešimir Krnjević and Kaufman, {Randal J.} and Peter Walter and Mauro Costa-Mattioli",
year = "2014",
month = "1",
day = "1",
doi = "10.1038/nn.3754",
language = "English (US)",
volume = "17",
pages = "1073--1082",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "8",

}

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

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

PY - 2014/1/1

Y1 - 2014/1/1

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 - http://www.scopus.com/inward/record.url?scp=84905106868&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84905106868&partnerID=8YFLogxK

U2 - 10.1038/nn.3754

DO - 10.1038/nn.3754

M3 - Article

C2 - 24974795

AN - SCOPUS:84905106868

VL - 17

SP - 1073

EP - 1082

JO - Nature Neuroscience

JF - Nature Neuroscience

SN - 1097-6256

IS - 8

ER -