eIF2α phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory

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 eIF2 alpha 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 eIF2 alpha phosphorylation in synaptic plasticity and behavioral learning. We show that in eIF2 alpha(+/S51A) mice, in which eIF2 alpha 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 eIF2 alpha phosphorylation is increased by injecting into the hippocampus a small molecule, Sal003, which prevents the dephosphorylation of eIF2 alpha. These findings highlight the importance of a single phosphorylation site in eIF2 alpha as a key regulator of L-LTP and LTM formation.