title: eIF2alpha phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory.
abstract: 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.
authors.affiliation: Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, Quebec, Canada. mauro.costa-mattioli@mail.mcgill.ca
authors.forename: Mauro
authors.initials: M
authors.lastname: Costa-Mattioli
authors.forename: Delphine
authors.initials: D
authors.lastname: Gobert
authors.forename: Elad
authors.initials: E
authors.lastname: Stern
authors.forename: Karine
authors.initials: K
authors.lastname: Gamache
authors.forename: Rodney
authors.initials: R
authors.lastname: Colina
authors.forename: Claudio
authors.initials: C
authors.lastname: Cuello
authors.forename: Wayne
authors.initials: W
authors.lastname: Sossin
authors.forename: Randal
authors.initials: R
authors.lastname: Kaufman
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
authors.forename: Kobi
authors.initials: K
authors.lastname: Rosenblum
authors.forename: Kresimir
authors.initials: K
authors.lastname: Krnjević
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Lacaille
authors.forename: Karim
authors.initials: K
authors.lastname: Nader
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
mesh_terms: 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
chemical_list: C081452:Atf4 protein, mouse; D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; C496827:salubrinal; D051701:Activating Transcription Factor 4; D013890:Thiourea