The late phase of long-term potentiation (LTP) and memory (LTM) requires new gene expression, but the molecular mechanisms that underlie these processes are not fully understood. Phosphorylation of eIF2alpha inhibits general translation but selectively stimulates translation of ATF4, a repressor of CREB-mediated late-LTP (L-LTP) and LTM. We used a pharmacogenetic bidirectional approach to examine the role of eIF2alpha phosphorylation in synaptic plasticity and behavioral learning. We show that in eIF2alpha(+/S51A) mice, in which eIF2alpha phosphorylation is reduced, the threshold for eliciting L-LTP in hippocampal slices is lowered, and memory is enhanced. In contrast, only early-LTP is evoked by repeated tetanic stimulation and LTM is impaired, when eIF2alpha phosphorylation is increased by injecting into the hippocampus a small molecule, Sal003, which prevents the dephosphorylation of eIF2alpha. These findings highlight the importance of a single phosphorylation site in eIF2alpha as a key regulator of L-LTP and LTM formation.

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Age-associated memory deterioration (and the decline in ability to acquire new information) is one of the major diseases of our era. Cognitive enhancement can be achieved by using psycho-stimulants, such as caffeine or nicotine, but very little is known about drugs that can enhance the consolidation phase of memories in the cortex, the brain structure considered to store, at least partially, long-term memories. We used cortex-dependent taste-learning paradigms to test the hypothesis that pharmacological manipulation of the translation initiation eIF2␣, which plays a role in hippocampus-dependent memory, can enhance positive or negative forms of taste memories. We found that dephosphorylation (Ser51) of eIF2␣, specifically in the cortex, is both correlated with and necessary for normal memory consolidation. To reduce eIF2␣ phosphorylation and improve memory consolidation, we pharmacologically inhibited one of the eIF2␣ kinases, PKR, which is known to be involved in brain aging and Alzheimer's disease. Systemic or local microinjection of PKR inhibitor to the gustatory cortex enhanced both positive and negative forms of taste memory in rats and mice. Our results provide clear evidence that PKR plays a major role in cortex-dependent memory consolidation and, therefore, that pharmacological inhibition of PKR is a potential target for drugs to enhance cognition. IntroductionSensory information in the mammalian brain is encoded, at least in part, in the relevant cortical area, but very little is known about pharmacological manipulations that could facilitate cortically dependent learning.From the temporal perspective, a given memory involves acquisition, consolidation, and retention phases, possibly followed by many cycles of relearning, reconsolidation, and reretention (for review, see Dudai, 2004; Alberini et al., 2006; Nader and Hardt, 2009; Alberini, 2011;Johansen et al., 2011). Memory consolidation, a process in which labile short-term memories are transformed over time into stable long-term memories, is divided into system and molecular consolidation; however, the connection between the two is not clear (Gildish et al., 2012). System consolidation is defined by the time frame in which a given brain structure (e.g., the hippocampus) is indispensable for normal memory retention, and is a very slow dynamic process (Johansen et al., 2011). Molecular consolidation is biochemically defined by the time frame in which pharmacological perturbations (e.g., by protein synthesis inhibitors) attenuate long-term but not shortterm memories.Recently, several studies, based on differing behavioral paradigms susbserved by different brain structures, demonstrated that molecular consolidation is mediated through complex regulation of mRNA translation (for reviews, see Costa-Mattioli et al., 2009a, b; Gkogkas et al., 2010; Gal-Ben-Ari and Rosenblum, 2011). As reviewed extensively (Sonenberg and Hinnebusch, 2009), translation regulation occurs during both the initiation and the elongation phases, and both phases are regulated duri...