title: p300/CBP-associated factor selectively regulates the extinction of conditioned fear.
abstract: It is well established that the activity of chromatin-modifying enzymes is crucial for regulating gene expression associated with hippocampal-dependent memories. However, very little is known about how these epigenetic mechanisms influence the formation of cortically dependent memory, particularly when there is competition between opposing memory traces, such as that which occurs during the acquisition and extinction of conditioned fear. Here we demonstrate, in C57BL/6 mice, that the activity of p300/CBP-associated factor (PCAF) within the infralimbic prefrontal cortex is required for long-term potentiation and is necessary for the formation of memory associated with fear extinction, but not for fear acquisition. Further, systemic administration of the PCAF activator SPV106 enhances memory for fear extinction and prevents fear renewal. The selective influence of PCAF on fear extinction is mediated, in part, by a transient recruitment of the repressive transcription factor ATF4 to the promoter of the immediate early gene zif268, which competitively inhibits its expression. Thus, within the context of fear extinction, PCAF functions as a transcriptional coactivator, which may facilitate the formation of memory for fear extinction by interfering with reconsolidation of the original memory trace.
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Australia 4072.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Coelho
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Roger
authors.initials: R
authors.lastname: Marek
authors.forename: Shanzhi
authors.initials: S
authors.lastname: Yan
authors.forename: Shawn
authors.initials: S
authors.lastname: Anderson
authors.forename: David
authors.initials: D
authors.lastname: Meyers
authors.forename: Chandrani
authors.initials: C
authors.lastname: Mukherjee
authors.forename: Gianluca
authors.initials: G
authors.lastname: Sbardella
authors.forename: Sabrina
authors.initials: S
authors.lastname: Castellano
authors.forename: Ciro
authors.initials: C
authors.lastname: Milite
authors.forename: Dante
authors.initials: D
authors.lastname: Rotili
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cole
authors.forename: Pankaj
authors.initials: P
authors.lastname: Sah
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kobor
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Bredy
mesh_terms: D000818:Animals; D003213:Conditioning, Psychological / Q000502:physiology*; D005108:Extinction, Psychological / Q000502:physiology*; D005239:Fear / Q000502:physiology* / Q000523:psychology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015534:Trans-Activators / Q000502:physiology; D050880:p300-CBP Transcription Factors / Q000502:physiology*; D000099224:p300-CBP-Associated Factor
chemical_list: D015534:Trans-Activators; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor