Blocking the eIF2α kinase (PKR) enhances positive and negative forms of cortex-dependent taste memory.

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 eIF2α, which plays a role in hippocampus-dependent memory, can enhance positive or negative forms of taste memories. We found that dephosphorylation (Ser51) of eIF2α, specifically in the cortex, is both correlated with and necessary for normal memory consolidation. To reduce eIF2α phosphorylation and improve memory consolidation, we pharmacologically inhibited one of the eIF2α 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.