p300/CBP-Associated Factor Selectively Regulates the Extinction of Conditioned Fear

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

doi:10.1523/jneurosci.0178-12.2012

Cited by 94Memory and Neural MechanismsNeuroscience and Neuropharmacology ResearchMemory Processes and Influences

p300/CBP-Associated Factor Selectively Regulates the Extinction of Conditioned Fear

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Wei, Wei, Coelho, Carlos M., Li, Xiang, Marek, Roger, Yan, Shanzhi, Anderson, Shawn, Meyers, David, Mukherjee, Chandrani +9 more·2012·The Journal of Neuroscience

DOI 10.1523/jneurosci.0178-12.2012PMC PMC3466419

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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.

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Threat extinction is associated with acetylation of histones near the Bdnf locus, changes to the p300/CBP complex (PCAF), and deposition of DNA-modification marks such as 5-hydroxymethylcytosine and N6-methyl-2'deoxyadenosine (m6dA) near loci of activity-dependent genes such as Bdnf.
“In the IL, threat extinction is associated with acetylation of histones near the Bdnf locus [61], changes to the p300/CBP complex (PCAF) [62], as well as deposition of DNA-modification marks such as 5-hydroxymethylcytosine and N6-methyl-2’deoxyadenosine (m6dA) near loci of activity-dependent genes such as Bdnf.”
From Prefrontal cortex, amygdala, and threat processing: implications for PTSD (2022) · cites this paper as [62]
Inhibition of PCAF in IL interferes with threat extinction.
“Additionally, inhibition of PCAF in IL was shown to interfere with threat extinction [62].”
From Prefrontal cortex, amygdala, and threat processing: implications for PTSD (2022) · cites this paper as [62]

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“In addition, injection of BDNF antibodies (anti-BDNF) in the IL prior to extinction training disrupts acquisition and retrieval of extinction memories while anti-BDNF infusions in the PL cortex do not affect extinction (Rosas-Vidal et al., 2014) (Table 9).”
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“Additionally, inhibition of PCAF in IL was shown to interfere with threat extinction [62].”
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Authors: 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.
Affiliations: The University of Queensland (AU)
University of British Columbia (CA)
Johns Hopkins University (US)
University of Salerno (IT)
Sapienza University of Rome (IT)
Corresponding author: Bredy, Timothy W.
ORCID: Wei, Wei
Coelho, Carlos M.
Li, Xiang
Marek, Roger
Meyers, David
Mukherjee, Chandrani
Sbardella, Gianluca
Castellano, Sabrina
Milite, Ciro
Rotili, Dante
Mai, Antonello
Cole, Philip A.
Sah, Pankaj
Kobor, Michael S.
Bredy, Timothy W.
Venue: The Journal of Neuroscience
Publisher: Society for Neuroscience
Published: 2012-08-29
Volume: 32
Issue: 35
Pages: 11930-11941
ISSN: 0270-6474 (ISSN-L)
1529-2401
DOI: 10.1523/jneurosci.0178-12.2012
PMC: PMC3466419
OpenAlex: W1998769481
Cited by: 93
References: 92
Citations by year: 2025: 4 · 2024: 6 · 2023: 3 · 2022: 5 · 2021: 3 · 2020: 3 · 2019: 8 · 2018: 4 · 2017: 5 · 2016: 15 · 2015: 9 · 2014: 15 · 2013: 13
FWCI: 6.06
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-sa
creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 183 d)
Locations: Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
Iris (Roma Tre University) (submittedVersion)
Funders: Australian Research Council (DP1096148)
National Health and Medical Research Council (1023127)
National Institute on Drug Abuse (K99DA026503)
Topics: Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Cognitive Neuroscience › Memory Processes and Influences
Keywords: PCAF, fear extinction, fear conditioning, infralimbic cortex, long-term potentiation, ATF4, Zif268, transcriptional coactivator, memory reconsolidation, fear renewal, chromatin modification
MeSH terms: p300-CBP-Associated Factor, Animals, Conditioning, Psychological, Extinction, Psychological, Fear, Humans, Male, Mice, Inbred C57BL, Trans-Activators, p300-CBP Transcription Factors, Mice, HEK293 Cells

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p300/CBP-Associated Factor Selectively Regulates the Extinction of Conditioned Fear

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