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 in memory destabilization 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 of memory at longer intervals after memory reactivation 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.
authors.affiliation: Center for Neural Science, New York University, New York, New York 10003.
authors.forename: Thu N
authors.initials: TN
authors.lastname: Huynh
authors.affiliation: Center for Neural Science, New York University, New York, New York 10003.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Santini
authors.affiliation: Center for Neural Science, New York University, New York, New York 10003 eklann@cns.nyu.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Klann
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology*; D003463:Cues; D004597:Electroshock; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors / Q000502:physiology; D039603:Eukaryotic Initiation Factor-4G / Q000037:antagonists & inhibitors / Q000502:physiology; D005239:Fear / Q000502:physiology*; D006835:Hydrazones; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D057567:Memory, Long-Term / Q000187:drug effects / Q000502:physiology; D011939:Mental Recall / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000502:physiology*; D009574:Nitro Compounds / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000172:deficiency / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C517852:4EGI-1 compound; D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G; D006835:Hydrazones; D007093:Imidazoles; D046912:Multiprotein Complexes; D009574:Nitro Compounds; C552719:PF-4708671; D010879:Piperazines; D013844:Thiazoles; D000076222:Mechanistic Target of Rapamycin Complex 1; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: consolidation; fear conditioning; long-term memory; mTORC1; reconsolidation; translation