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

Abstract

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.

Translational control by eIF2α in neurons: Beyond the stress response

“…Conversely, the chemical increase of PKR dependent eIF2α phosphorylation in hippocampal neurons elevated ATF4 translation and suppressed CREB‐dependent gene expression, inhibiting LTP formation [Jiang et al, ]. The involvement of HRI was suggested using an object recognition model of memory, in which the authors observed a transient increase in the phosphorylation of eIF2α in dorsal CA1 that was dependent on HRI [ILL‐Raga et al, ].…”

Rôle de l’heme regulated inhibitor(HRI) dans la résistance à l’apoptose

“…Des études de relations structure-activité ont permis d'améliorer les propriétés pharmacodynamiques de la molécule de départ. Par ailleurs, l'utilisation de ces nouveaux dérivés a permis l'étude du rôle de HRI dans la plasticité synaptique lors de tests d'apprentissage effectués chez le rat, suggérant que HRI peut être ciblée de façon pharmacologique [44]. Des études plus poussées devront cependant être réalisées afin de tester la spécificité de ces drogues et d'optimiser leurs propriétés thérapeutiques potentielles.…”

Activating transcription factor 4 (ATF4) modulates post-synaptic development and dendritic spine morphology

“…Several studies in mice have also been interpreted to indicate that ATF4 impairs LTP and memory consolidation (Chen et al, 2003; Costa-Mattioli et al, 2005, 2007; Jiang et al, 2010). On the other hand, additional reports suggest that ATF4 is required for behavioral flexibility (Trinh et al, 2012) and consolidation of object recognition memory (Ill-Raga et al, 2013) and enhances memory for fear extinction (Wei et al, 2012). The apparently diverging views of ATF4's role in learning and memory may reflect the use of indirect and likely non-selective means that have been used to experimentally affect ATF4 expression.…”