Consolidation of object recognition memory requires HRI kinase-dependent phosphorylation of eIF2α in the hippocampus

Local control of protein synthesis at synapses is crucial for synaptic plasticity and memory formation. However, little is known about the signals coupling neurotransmitter release with the translational machinery during these processes. Here, we studied the involvement of heme-regulated inhibitor (HRI) kinase, a kinase activated by nitric oxide that phosphorylates eukaryotic initiation factor 2α (eIF2α), in object recognition (OR) memory consolidation. Phosphorylated eIF2α mediates two opposing effects upon translation: translational arrest of most mRNAs and translational activation of selected mRNAs bearing specific features in their 5'untranslated regions (5'UTRs). We found that HRI kinase activation in the CA1 region of the dorsal hippocampus is necessary for retention of OR memory in rats. Accordingly, learning induced a transient increase in the phosphorylation state of eIF2α in dorsal CA1 which was abolished by the HRI kinase inhibitor N-(2,6-dimethylbenzyl)-6,7-dimethoxy-2H-[1]benzofuro[3,2-c]pyrazol-3-amine hydrochloride (AMI). The increase in p-eIF2α was associated with increased expression of BACE1 and activating transcription factor 4, two proteins containing eIF2α-responsive 5'UTRs in their mRNAs that play a key role in synaptic plasticity. Our data suggests that learning promotes the transient phosphorylation of eIF2α to allow for translation of specific 5'UTR-mRNAs through a process requiring HRI kinase activation.