Reversible phosphorylation of subunit of eIF2 on Ser51 is one of the best characterized rate-limiting steps at the translational initiation level, and it controls the rates of both gene-specific translation and general translation. Ser51 phosphorylation of eIF2 precludes formation of eIF2GTPMet-tRNAiMet ternary complex and thus blocks general translation initiation. Paradoxically, the decrease in ternary complexes stimulates translation of specific mRNAs, including activating transcription factor 4 (ATF4). However, upon training-induced eIF2 dephosphorylation, it remains unclear which translation mechanisms, general translation or gene-specific translation, efficiently gates the transition from short-term memory to long-term memory formation. To address this issue, we generated and analyzed a conditional double-stranded RNA-dependent protein kinase (PKR) transgenic mouse strain, in which translation of a particular protein ATF4 through eIF2 phosphorylation in the hippocampal CA1 neurons was enhanced by a chemical inducer. This year we found that gene-specific translation, including ATF4 and its downstream molecular pathway, in CA1 pyramidal cells is critical for long-term memory formation and plasticity. Importantly, although we observed significant behavioral deficits, overall levels of protein synthesis in CA1 were not changed after PKR activation. Conversely, inhibition of general translation by low-dose anisomycin failed to block hippocampal-dependent memory consolidation. Taken together, these results suggest that consolidation of hippocampal memories through eIF2 dephosphorylation efficiently recruits transcription/translation of particular genes, including ATF4 and BDNF, in CA1 pyramidal cells rather than inducing an overall increase in the activity of basic translational machinery. The present study sheds light on the critical importance of gene-specific translations for hippocampal memory consolidation.
| Jiang, Zhihong; Belforte, Juan E; Lu, Yuan et al. (2010) eIF2alpha Phosphorylation-dependent translation in CA1 pyramidal cells impairs hippocampal memory consolidation without affecting general translation. J Neurosci 30:2582-94 |
| Je, Hyun-Soo; Lu, Yuan; Yang, Feng et al. (2009) Chemically inducible inactivation of protein synthesis in genetically targeted neurons. J Neurosci 29:6761-6 |
