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

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

doi:10.1038/nn.3754

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

Nat Neurosci. 2014 Aug;17(8):1073-82. doi: 10.1038/nn.3754. Epub 2014 Jun 29.

Affiliations

¹ 1] Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA. [2] Memory and Brain Research Center, Baylor College of Medicine, Houston, Texas, USA. [3].
² 1] Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA. [2] Memory and Brain Research Center, Baylor College of Medicine, Houston, Texas, USA.
³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
⁴ 1] Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA. [2] Present address: Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, Georgia, USA.
⁵ Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California, USA.
⁶ Department of Physiology, McGill University, Montreal, Quebec, Canada.
⁷ Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.

PMID: 24974795
PMCID: PMC4340591
DOI: 10.1038/nn.3754

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Eukaryotic Initiation Factor-2 / genetics*
Eukaryotic Initiation Factor-2 / metabolism*
Gene Expression Regulation
Learning / physiology*
Long-Term Synaptic Depression / genetics*
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Phosphorylation / genetics
Protein Biosynthesis*
Receptors, AMPA / deficiency
Receptors, AMPA / physiology*
Receptors, Metabotropic Glutamate / metabolism*
Space Perception / physiology

Substances

Eukaryotic Initiation Factor-2
Receptors, AMPA
Receptors, Metabotropic Glutamate

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

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Grants and funding