P300/CBP-associated factor selectively regulates the extinction of conditioned fear

Wei Wei, Carlos M. Coelho, Xiang Li, Roger Marek, Shanzhi Yan, Shawn Anderson, David Meyers, Chandrani Mukherjee, Gianluca Sbardella, Sabrina Castellano, Ciro Milite, Dante Rotili, Antonello Mai, Philip A. Cole, Pankaj Sah, Michael S. Kobor, Timothy W. Bredy

Research output: Contribution to journalArticle

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/6mice, that the activityofp300/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 ATF4tothe promoter of the immediate early genezif268, 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.

Original languageEnglish (US)
Pages (from-to)11930-11941
Number of pages12
JournalJournal of Neuroscience
Volume32
Issue number35
DOIs
StatePublished - Aug 29 2012

ASJC Scopus subject areas

  • Neuroscience(all)

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    Wei, W., Coelho, C. M., Li, X., Marek, R., Yan, S., Anderson, S., Meyers, D., Mukherjee, C., Sbardella, G., Castellano, S., Milite, C., Rotili, D., Mai, A., Cole, P. A., Sah, P., Kobor, M. S., & Bredy, T. W. (2012). P300/CBP-associated factor selectively regulates the extinction of conditioned fear. Journal of Neuroscience, 32(35), 11930-11941. https://doi.org/10.1523/JNEUROSCI.0178-12.2012