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.
authors: 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].
authors: Gonzalo Viana
authors: GV
authors: Di Prisco
authors: 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].
authors: Wei
authors: W
authors: Huang
authors: 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].
authors: Shelly A
authors: 0000000171330064
authors: SA
authors: Buffington
authors: 1] Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA. [2] Memory and Brain Research Center, Baylor College of Medicine, Houston, Texas, USA.
authors: Chih-Chun
authors: CC
authors: Hsu
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors: Penelope E
authors: PE
authors: Bonnen
authors: 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.
authors: Andon N
authors: AN
authors: Placzek
authors: Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California, USA.
authors: Carmela
authors: C
authors: Sidrauski
authors: Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors: Krešimir
authors: K
authors: Krnjević
authors: Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors: Randal J
authors: RJ
authors: Kaufman
authors: Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California, USA.
authors: Peter
authors: P
authors: Walter
authors: 1] Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA. [2] Memory and Brain Research Center, Baylor College of Medicine, Houston, Texas, USA.
authors: Mauro
authors: M
authors: Costa-Mattioli
mesh_terms: D000818:Animals; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D007858:Learning / Q000502:physiology*; D036881:Long-Term Synaptic Depression / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000235:genetics; D014176:Protein Biosynthesis; D018091:Receptors, AMPA / Q000172:deficiency / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013028:Space Perception / Q000502:physiology
chemical_list: D015852:Eukaryotic Initiation Factor-2; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate