eIF2alpha 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 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.
Costa-Mattioli
Mauro
M
Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, Quebec, Canada. mauro.costa-mattioli@mail.mcgill.ca
Gobert
Delphine
D
Stern
Elad
E
Gamache
Karine
K
Colina
Rodney
R
Cuello
Claudio
C
Sossin
Wayne
W
Kaufman
Randal
R
Pelletier
Jerry
J
Rosenblum
Kobi
K
Krnjević
Kresimir
K
Lacaille
Jean-Claude
JC
Nader
Karim
K
Sonenberg
Nahum
N
D051701:Activating Transcription Factor 4 / Q000235:genetics; D019943:Amino Acid Substitution; D000818:Animals; D001306:Auditory Pathways / Q000502:physiology; D001921:Brain / Q000033:anatomy & histology / Q000502:physiology; D002934:Cinnamates / Q000494:pharmacology; D003213:Conditioning, Psychological; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005239:Fear / Q000502:physiology; D015870:Gene Expression; D006624:Hippocampus / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008568:Memory / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis; D013569:Synapses / Q000502:physiology*; D013649:Taste / Q000502:physiology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
C081452:Atf4 protein, mouse; D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; C496827:salubrinal; D051701:Activating Transcription Factor 4; D013890:Thiourea