title: eIF2alpha Phosphorylation-dependent translation in CA1 pyramidal cells impairs hippocampal memory consolidation without affecting general translation.
abstract: Protein synthesis inhibitor antibiotics are widely used to produce amnesia, and have been recognized to inhibit general or global mRNA translation in the basic translational machinery. For instance, anisomycin interferes with protein synthesis by inhibiting peptidyl transferase or the 80S ribosomal function. Therefore, de novo general or global protein synthesis has been thought to be necessary for long-term memory formation. However, it is unclear which mode of translation-gene-specific translation or general/global translation-is actually crucial for the memory consolidation process in mammalian brains. Here, we generated a conditional transgenic mouse strain in which double-strand RNA-dependent protein kinase (PKR)-mediated phosphorylation of eIF2alpha, a key translation initiation protein, was specifically increased in hippocampal CA1 pyramidal cells by the chemical inducer AP20187. Administration of AP20187 significantly increased activating transcription factor 4 (ATF4) translation and concomitantly suppressed CREB-dependent pathways in CA1 cells; this led to impaired hippocampal late-phase LTP and memory consolidation, with no obvious reduction in general translation. Conversely, inhibition of general translation by low-dose anisomycin failed to block hippocampal-dependent memory consolidation. Together, these results indicated that CA1-restricted genetic manipulation of particular mRNA translations is sufficient to impair the consolidation and that consolidation of memories in CA1 pyramidal cells through eIF2alpha dephosphorylation depends more on transcription/translation of particular genes than on overall levels of general translation. The present study sheds light on the critical importance of gene-specific translations for hippocampal memory consolidation.
authors.affiliation: Unit on the Genetics of Cognition and Behavior, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Jiang
authors.forename: Juan E
authors.initials: JE
authors.lastname: Belforte
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lu
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yabe
authors.forename: James
authors.initials: J
authors.lastname: Pickel
authors.forename: Carolyn Beebe
authors.initials: CB
authors.lastname: Smith
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Je
authors.forename: Bai
authors.initials: B
authors.lastname: Lu
authors.forename: Kazu
authors.initials: K
authors.lastname: Nakazawa
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D001703:Biophysics; D050882:CREB-Binding Protein / Q000378:metabolism; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D005239:Fear / Q000523:psychology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000473:pathology*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D018709:Statistics, Nonparametric; D013266:Stilbamidines / Q000378:metabolism; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D000073940:Transcription Factor 4
chemical_list: C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; C463061:AP20187; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015852:Eukaryotic Initiation Factor-2; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D011500:Protein Synthesis Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D013266:Stilbamidines; C090743:Tcf4 protein, mouse; D000073940:Transcription Factor 4; D000841:Anisomycin; D050882:CREB-Binding Protein; D011494:Protein Kinases; D016559:Tacrolimus