eIF2α 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 eIF2␣, 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 eIF2␣ 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.

Inhibition of the interactions between eukaryotic initiation factors 4E and 4G impairs long-term associative memory consolidation but not reconsolidation

“…Because even total blockade of eIF4E-eIF4G interactions would not be expected to block all protein synthesis, this level of protein synthesis reduction was not surprising (5,17,18). However, our results are interesting in the context of previous studies because we found significant memory impairments at levels of protein synthesis blockade below those (either presumed or measured) in previous studies using other protein synthesis inhibitors (12,13,19). Furthermore, these findings combined with a recent report showing that consolidation was more effectively and persistently blocked by anisomycin than was reconsolidation (20) are consistent with our findings of increased eIF4F formation following memory acquisition but not reactivation (Fig.…”

Translational Control Mechanisms in Long-lasting Synaptic Plasticity and Memory

“…Recent evidence supports the idea that eIF2␣ phosphorylation regulates L-LTP and LTM storage through translational control of specific mRNAs, such as ATF4 mRNA. For instance, although general translation is not altered in CA1 neurons, ATF4 protein is increased in the CA1 region from mice in which eIF2␣ is phosphorylated (27). Consistent with these data, Sal003, which increases eIF2␣ phosphorylation, failed to suppress L-LTP in slices from ATF4 knock-out mice compared with WT mice (17).…”

“…Conversely, hippocampal infusion with a small molecule inhibitor (Sal003), which prevents eIF2␣ dephosphorylation, blocks both L-LTP and LTM formation (17). Jiang et al (27) recently ruled out the possibility that the effects of eIF2␣ phosphorylation on LTM and LTP occur during development. Using a new pharmacogenetic mouse model in which eIF2␣ phosphorylation is selectively increased in CA1 hippocampal neurons (from adult animals) in a time-dependent and inducible manner, they demonstrated that both L-LTP and LTM were impaired (27).…”

PKR Inhibition Rescues Memory Deficit and ATF4 Overexpression in ApoE ε4 Human Replacement Mice

“…Indeed, eIF2␣-KI mice expressed significantly lower ATF4 mRNA levels in the hippocampus compared with WT littermates (eIF2␣-KI, n ϭ 11; eIF2␣-WT, n ϭ 9; t (18) ϭ 2.4, p ϭ 0.03; Fig. 2D), surprisingly demonstrating that a prolonged reduction in phosphorylation levels of eIF2␣ has a bidirectional effect specifically on the transcription of ATF4 (Jiang et al, 2010;Trinh et al, 2012).…”