title: eIF2α-mediated translational control regulates the persistence of cocaine-induced LTP in midbrain dopamine neurons.
abstract: Recreational drug use leads to compulsive substance abuse in some individuals. Studies on animal models of drug addiction indicate that persistent long-term potentiation (LTP) of excitatory synaptic transmission onto ventral tegmental area (VTA) dopamine (DA) neurons is a critical component of sustained drug seeking. However, little is known about the mechanism regulating such long-lasting changes in synaptic strength. Previously, we identified that translational control by eIF2α phosphorylation (p-eIF2α) regulates cocaine-induced LTP in the VTA (Huang et al., 2016). Here we report that in mice with reduced p-eIF2α-mediated translation, cocaine induces persistent LTP in VTA DA neurons. Moreover, selectively inhibiting eIF2α-mediated translational control with a small molecule ISRIB, or knocking downoligophrenin-1-an mRNA whose translation is controlled by p-eIF2α-in the VTA also prolongs cocaine-induced LTP. This persistent LTP is mediated by the insertion of GluR2-lacking AMPARs. Collectively, our findings suggest that eIF2α-mediated translational control regulates the progression from transient to persistent cocaine-induced LTP.
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, United States.|Memory and Brain Research Center, Baylor College of Medicine, Houston, United States.
authors.forename: Andon N
authors.initials: AN
authors.lastname: Placzek
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, United States.|Memory and Brain Research Center, Baylor College of Medicine, Houston, United States.
authors.forename: Gonzalo Viana Di
authors.initials: GV
authors.lastname: Prisco
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, United States.|Memory and Brain Research Center, Baylor College of Medicine, Houston, United States.|Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Khatiwada
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, United States.|Memory and Brain Research Center, Baylor College of Medicine, Houston, United States.
authors.forename: Martina
authors.initials: M
authors.lastname: Sgritta
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, United States.|Memory and Brain Research Center, Baylor College of Medicine, Houston, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Physiology, McGill University, Montreal, Canada.
authors.forename: Krešimir
authors.initials: K
authors.lastname: Krnjević
authors.affiliation: Degenerative Diseases Program, SBP Medical Discovery Institute, La Jolla, United States.
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.affiliation: Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School of Medicine, Philadelphia, United States.
authors.forename: John A
authors.initials: JA
authors.lastname: Dani
authors.affiliation: Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Walter
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, United States.|Memory and Brain Research Center, Baylor College of Medicine, Houston, United States.
authors.forename: Mauro
authors.initials: M
authors.lastname: Costa-Mattioli
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D003042:Cocaine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D051379:Mice; D014176:Protein Biosynthesis; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology*
chemical_list: D018765:Dopamine Uptake Inhibitors; D015852:Eukaryotic Initiation Factor-2; D003042:Cocaine
keywords: AMPAR; drug addiciton; mouse; neuroscience; protein synthesis; psychostimulant abuse; synaptic plasticity