Requirement of mammalian target of rapamycin complex 1 downstream effectors in cued fear memory reconsolidation and its persistence

Thu N. Huynh, Emanuela Santini, Eric Klann

Research output: Contribution to journalArticle

Abstract

Memory retrieval, often termed reconsolidation, can render previously consolidated memories susceptible to manipulation that can lead to alterations in memory strength. Although it is known that reconsolidation requires mammalian target of rapamycin complex 1 (mTORC1)-dependent translation, the specific contributions of its downstream effectors in reconsolidation are unclear. Using auditory fear conditioning in mice, we investigated the role of eukaryotic translation initiation factor 4E (eIF4E)- eIF4G interactions and p70 S6 kinase polypeptide 1 (S6K1) in reconsolidation. We found that neither 4EGI-1 (2-[(4-(3,4-dichlorophenyl)-thiazol-2-ylhydrazono)-3-(2- nitrophenyl)]propionic acid), an inhibitor of eFI4E- eIF4G interactions, nor PF-4708671 [2-((4-(5-ethylpyrimidin-4-yl)piperazin-1- yl)methyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole], an inhibitor of S6K1, alone blocked the reconsolidation of auditory fear memory. In contrast, using these drugs in concert to simultaneously block eIF4E- eIF4G interactions and S6K1 immediately after memory reactivation significantly attenuated fear memory reconsolidation. Moreover, the combination of 4EGI-1 and PF-4708671 further destabilized fear memory 10 d after memory reactivation, which was consistent with experiments using rapamycin, an mTORC1 inhibitor. Furthermore, inhibition of S6K1 immediately after retrieval resulted inmemorydestabilization 10 d after reactivation, whereas inhibition of eIF4E- eIF4G interactions did not. These results indicate that the reconsolidation of fear memory requires concomitant association of eIF4E to eIF4G as well as S6K1 activity and that the persistence ofmemoryat longer intervals aftermemoryreactivation also requires mTORC1-dependent processes that involve S6K1. These findings suggest a potential mechanism for how mTORC1-dependent translation is fine tuned to alter memory persistence.

Original languageEnglish (US)
Pages (from-to)9034-9039
Number of pages6
JournalJournal of Neuroscience
Volume34
Issue number27
DOIs
StatePublished - 2014

Fingerprint

Fear
Ribosomal Protein S6 Kinases
Eukaryotic Initiation Factor-4E
Eukaryotic Initiation Factors
Peptides
mechanistic target of rapamycin complex 1
70-kDa Ribosomal Protein S6 Kinases
Sirolimus
Pharmaceutical Preparations

Keywords

  • Consolidation
  • Fear conditioning
  • Long-term memory
  • MTORC1
  • Reconsolidation
  • Translation

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Requirement of mammalian target of rapamycin complex 1 downstream effectors in cued fear memory reconsolidation and its persistence. / Huynh, Thu N.; Santini, Emanuela; Klann, Eric.

In: Journal of Neuroscience, Vol. 34, No. 27, 2014, p. 9034-9039.

Research output: Contribution to journalArticle

@article{e336039727dc422dafe393cb0e0074a0,
title = "Requirement of mammalian target of rapamycin complex 1 downstream effectors in cued fear memory reconsolidation and its persistence",
abstract = "Memory retrieval, often termed reconsolidation, can render previously consolidated memories susceptible to manipulation that can lead to alterations in memory strength. Although it is known that reconsolidation requires mammalian target of rapamycin complex 1 (mTORC1)-dependent translation, the specific contributions of its downstream effectors in reconsolidation are unclear. Using auditory fear conditioning in mice, we investigated the role of eukaryotic translation initiation factor 4E (eIF4E)- eIF4G interactions and p70 S6 kinase polypeptide 1 (S6K1) in reconsolidation. We found that neither 4EGI-1 (2-[(4-(3,4-dichlorophenyl)-thiazol-2-ylhydrazono)-3-(2- nitrophenyl)]propionic acid), an inhibitor of eFI4E- eIF4G interactions, nor PF-4708671 [2-((4-(5-ethylpyrimidin-4-yl)piperazin-1- yl)methyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole], an inhibitor of S6K1, alone blocked the reconsolidation of auditory fear memory. In contrast, using these drugs in concert to simultaneously block eIF4E- eIF4G interactions and S6K1 immediately after memory reactivation significantly attenuated fear memory reconsolidation. Moreover, the combination of 4EGI-1 and PF-4708671 further destabilized fear memory 10 d after memory reactivation, which was consistent with experiments using rapamycin, an mTORC1 inhibitor. Furthermore, inhibition of S6K1 immediately after retrieval resulted inmemorydestabilization 10 d after reactivation, whereas inhibition of eIF4E- eIF4G interactions did not. These results indicate that the reconsolidation of fear memory requires concomitant association of eIF4E to eIF4G as well as S6K1 activity and that the persistence ofmemoryat longer intervals aftermemoryreactivation also requires mTORC1-dependent processes that involve S6K1. These findings suggest a potential mechanism for how mTORC1-dependent translation is fine tuned to alter memory persistence.",
keywords = "Consolidation, Fear conditioning, Long-term memory, MTORC1, Reconsolidation, Translation",
author = "Huynh, {Thu N.} and Emanuela Santini and Eric Klann",
year = "2014",
doi = "10.1523/JNEUROSCI.0878-14.2014",
language = "English (US)",
volume = "34",
pages = "9034--9039",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "27",

}

TY - JOUR

T1 - Requirement of mammalian target of rapamycin complex 1 downstream effectors in cued fear memory reconsolidation and its persistence

AU - Huynh, Thu N.

AU - Santini, Emanuela

AU - Klann, Eric

PY - 2014

Y1 - 2014

N2 - Memory retrieval, often termed reconsolidation, can render previously consolidated memories susceptible to manipulation that can lead to alterations in memory strength. Although it is known that reconsolidation requires mammalian target of rapamycin complex 1 (mTORC1)-dependent translation, the specific contributions of its downstream effectors in reconsolidation are unclear. Using auditory fear conditioning in mice, we investigated the role of eukaryotic translation initiation factor 4E (eIF4E)- eIF4G interactions and p70 S6 kinase polypeptide 1 (S6K1) in reconsolidation. We found that neither 4EGI-1 (2-[(4-(3,4-dichlorophenyl)-thiazol-2-ylhydrazono)-3-(2- nitrophenyl)]propionic acid), an inhibitor of eFI4E- eIF4G interactions, nor PF-4708671 [2-((4-(5-ethylpyrimidin-4-yl)piperazin-1- yl)methyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole], an inhibitor of S6K1, alone blocked the reconsolidation of auditory fear memory. In contrast, using these drugs in concert to simultaneously block eIF4E- eIF4G interactions and S6K1 immediately after memory reactivation significantly attenuated fear memory reconsolidation. Moreover, the combination of 4EGI-1 and PF-4708671 further destabilized fear memory 10 d after memory reactivation, which was consistent with experiments using rapamycin, an mTORC1 inhibitor. Furthermore, inhibition of S6K1 immediately after retrieval resulted inmemorydestabilization 10 d after reactivation, whereas inhibition of eIF4E- eIF4G interactions did not. These results indicate that the reconsolidation of fear memory requires concomitant association of eIF4E to eIF4G as well as S6K1 activity and that the persistence ofmemoryat longer intervals aftermemoryreactivation also requires mTORC1-dependent processes that involve S6K1. These findings suggest a potential mechanism for how mTORC1-dependent translation is fine tuned to alter memory persistence.

AB - Memory retrieval, often termed reconsolidation, can render previously consolidated memories susceptible to manipulation that can lead to alterations in memory strength. Although it is known that reconsolidation requires mammalian target of rapamycin complex 1 (mTORC1)-dependent translation, the specific contributions of its downstream effectors in reconsolidation are unclear. Using auditory fear conditioning in mice, we investigated the role of eukaryotic translation initiation factor 4E (eIF4E)- eIF4G interactions and p70 S6 kinase polypeptide 1 (S6K1) in reconsolidation. We found that neither 4EGI-1 (2-[(4-(3,4-dichlorophenyl)-thiazol-2-ylhydrazono)-3-(2- nitrophenyl)]propionic acid), an inhibitor of eFI4E- eIF4G interactions, nor PF-4708671 [2-((4-(5-ethylpyrimidin-4-yl)piperazin-1- yl)methyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole], an inhibitor of S6K1, alone blocked the reconsolidation of auditory fear memory. In contrast, using these drugs in concert to simultaneously block eIF4E- eIF4G interactions and S6K1 immediately after memory reactivation significantly attenuated fear memory reconsolidation. Moreover, the combination of 4EGI-1 and PF-4708671 further destabilized fear memory 10 d after memory reactivation, which was consistent with experiments using rapamycin, an mTORC1 inhibitor. Furthermore, inhibition of S6K1 immediately after retrieval resulted inmemorydestabilization 10 d after reactivation, whereas inhibition of eIF4E- eIF4G interactions did not. These results indicate that the reconsolidation of fear memory requires concomitant association of eIF4E to eIF4G as well as S6K1 activity and that the persistence ofmemoryat longer intervals aftermemoryreactivation also requires mTORC1-dependent processes that involve S6K1. These findings suggest a potential mechanism for how mTORC1-dependent translation is fine tuned to alter memory persistence.

KW - Consolidation

KW - Fear conditioning

KW - Long-term memory

KW - MTORC1

KW - Reconsolidation

KW - Translation

UR - http://www.scopus.com/inward/record.url?scp=84903625342&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84903625342&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.0878-14.2014

DO - 10.1523/JNEUROSCI.0878-14.2014

M3 - Article

C2 - 24990923

AN - SCOPUS:84903625342

VL - 34

SP - 9034

EP - 9039

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 27

ER -