eIF2α phosphorylation-dependent translation in CA1 pyramidal cells impairs hippocampal memory consolidation without affecting general translation
| Autor: | Zhihong Jiang, Yoko Yabe, James Pickel, Bai Lu, Kazu Nakazawa, Juan E. Belforte, Yuan Lu, Hyunsoo Shawn Je, Carolyn Beebe Smith |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Patch-Clamp Techniques
Stilbamidines Eukaryotic Initiation Factor-2 Long-Term Potentiation Biophysics Mice Transgenic Biology Hippocampal formation In Vitro Techniques Hippocampus Article Statistics Nonparametric Tacrolimus chemistry.chemical_compound Mice Eukaryotic translation Transcription Factor 4 Conditioning Psychological Protein biosynthesis Avoidance Learning Animals Phosphorylation Maze Learning Anisomycin Protein Synthesis Inhibitors Analysis of Variance Memory Disorders Dose-Response Relationship Drug Basic Helix-Loop-Helix Leucine Zipper Transcription Factors General Neuroscience Pyramidal Cells Long-term potentiation Translation (biology) Fear Protein kinase R CREB-Binding Protein Electric Stimulation Enzyme Activation chemistry Gene Expression Regulation Mutation Memory consolidation Neuroscience Microtubule-Associated Proteins Protein Kinases Proto-Oncogene Proteins c-fos Signal Transduction |
| Popis: | 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 novogeneral 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 eIF2α, 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 eIF2α 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. |
| Databáze: | OpenAIRE |
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