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 eIF2α 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 eIF2α phosphorylation in synaptic plasticity and behavioral learning. We show that in eIF2α+/S51A mice, in which eIF2α 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 eIF2α phosphorylation is increased by injecting into the hippocampus a small molecule, Sal003, which prevents the dephosphorylation of eIF2α. These findings highlight the importance of a single phosphorylation site in eIF2α as a key regulator of L-LTP and LTM formation.
Bibliographical noteFunding Information:
We thank R. Darnell, A. Fine, R. Blitzer, R. Kelleher, A. Koromilas, C. Alberini, Y. Dudai, and M. Fabian for comments on the manuscript; A. Rosenfeld, M. Bidinosti, and R. Dowling for proofreading; T. Townes for providing the ATF4 −/− mice; A. LaFrance for assisting in the maintenance of the eIF2α +/S51A mice; T. Lawson, N. Taheri, and C. Lister for excellent assistance. This work was supported by a Team grant from the Canadian Institute of Health Research (CIHR) to N.S., K.N., J.P., J.-C.L., and M.C.-M, a Howard Hughes Medical Institute (HHMI) grant to N.S., an NIH grant to R.K., a CIHR and an EJLB Foundation grant to K.N., and an ISF for K.R. N.S. is an HHMI International scholar. M.C.-M. was supported by a CIHR postdoctoral fellowship.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology (all)