eIF2α Phosphorylation Bidirectionally Regulates the Switch from Short- to Long-Term Synaptic Plasticity and Memory

Mauro Costa-Mattioli; Delphine Gobert; Elad Stern; Karine Gamache; Rodney Colina; Claudio Cuello; Wayne Sossin; Randal Kaufman; Jerry Pelletier; Kobi Rosenblum; Krešimir Krnjević; Jean Claude Lacaille; Karim Nader; Nahum Sonenberg

doi:10.1016/j.cell.2007.01.050

eIF2α Phosphorylation Bidirectionally Regulates the Switch from Short- to Long-Term Synaptic Plasticity and Memory

Mauro Costa-Mattioli, Delphine Gobert, Elad Stern, Karine Gamache, Rodney Colina, Claudio Cuello, Wayne Sossin, Randal Kaufman, Jerry Pelletier, Kobi Rosenblum, Krešimir Krnjević, Jean Claude Lacaille, Karim Nader, Nahum Sonenberg

Department of Neurobiology

Research output: Contribution to journal › Article › peer-review

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 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.

Original language	English
Pages (from-to)	195-206
Number of pages	12
Journal	Cell
Volume	129
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2007.01.050
State	Published - 6 Apr 2007

Bibliographical note

Funding 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.

Keywords

MOLNEURO
RNA
SYSNEURO

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.cell.2007.01.050

Cite this

Costa-Mattioli, M., Gobert, D., Stern, E., Gamache, K., Colina, R., Cuello, C., Sossin, W., Kaufman, R., Pelletier, J., Rosenblum, K., Krnjević, K., Lacaille, J. C., Nader, K., & Sonenberg, N. (2007). eIF2α Phosphorylation Bidirectionally Regulates the Switch from Short- to Long-Term Synaptic Plasticity and Memory. Cell, 129(1), 195-206. https://doi.org/10.1016/j.cell.2007.01.050

@article{6429dfb70a954c648d038c926d7ad1a5,

title = "eIF2α 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 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.",

keywords = "MOLNEURO, RNA, SYSNEURO",

author = "Mauro Costa-Mattioli and Delphine Gobert and Elad Stern and Karine Gamache and Rodney Colina and Claudio Cuello and Wayne Sossin and Randal Kaufman and Jerry Pelletier and Kobi Rosenblum and Kre{\v s}imir Krnjevi{\'c} and Lacaille, {Jean Claude} and Karim Nader and Nahum Sonenberg",

note = "Funding 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. ",

year = "2007",

month = apr,

day = "6",

doi = "10.1016/j.cell.2007.01.050",

language = "English",

volume = "129",

pages = "195--206",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "1",

}

Costa-Mattioli, M, Gobert, D, Stern, E, Gamache, K, Colina, R, Cuello, C, Sossin, W, Kaufman, R, Pelletier, J, Rosenblum, K, Krnjević, K, Lacaille, JC, Nader, K & Sonenberg, N 2007, 'eIF2α Phosphorylation Bidirectionally Regulates the Switch from Short- to Long-Term Synaptic Plasticity and Memory', Cell, vol. 129, no. 1, pp. 195-206. https://doi.org/10.1016/j.cell.2007.01.050

TY - JOUR

T1 - eIF2α Phosphorylation Bidirectionally Regulates the Switch from Short- to Long-Term Synaptic Plasticity and Memory

AU - Costa-Mattioli, Mauro

AU - Gobert, Delphine

AU - Stern, Elad

AU - Gamache, Karine

AU - Colina, Rodney

AU - Cuello, Claudio

AU - Sossin, Wayne

AU - Kaufman, Randal

AU - Pelletier, Jerry

AU - Rosenblum, Kobi

AU - Krnjević, Krešimir

AU - Lacaille, Jean Claude

AU - Nader, Karim

AU - Sonenberg, Nahum

N1 - Funding 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.

PY - 2007/4/6

Y1 - 2007/4/6

N2 - 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.

AB - 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.

KW - MOLNEURO

KW - RNA

KW - SYSNEURO

UR - http://www.scopus.com/inward/record.url?scp=33947719749&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2007.01.050

DO - 10.1016/j.cell.2007.01.050

M3 - Article

C2 - 17418795

AN - SCOPUS:33947719749

SN - 0092-8674

VL - 129

SP - 195

EP - 206

JO - Cell

JF - Cell

IS - 1

ER -

eIF2α Phosphorylation Bidirectionally Regulates the Switch from Short- to Long-Term Synaptic Plasticity and Memory

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this