Journal
NEUROPHARMACOLOGY
Volume 116, Issue -, Pages 188-195Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2016.12.023
Keywords
Posttraumatic stress; FKBP5; mRNA; Threat extinction; Fear extinction; Dexamethasone; Resilience; Translational model; Latent growth mixture modeling
Categories
Funding
- Howard Hughes Medical Institute, NIH [R01MH096764]
- NIH/NCRR base grant [P51RR000165]
- NARSAD Young Investigator Grant [22434]
- Spanish grants from the Ministerio de Economia, Industria y Competitividad: Ramon y Cajal programme [RYC-2014-15784, SAF2016-76565-R]
- National Institute of Mental Health [K01MH102415]
- NARSAD Young Investigator Grant
- [R21MH101492-01]
- [R21MH092576]
- [R01MH100122]
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Deficits in fear extinction learning are hypothesized to underlie the development of posttraumatic stress disorder (PTSD). Such deficits may, in part, be due to genetic and epigenetic variation in the stress related gene FKBP5. Conversely, altering FKBP5 epigenetic responses during memory consolidation may rescue extinction deficits making it a target for acute intervention to prevent the development of PTSD. Study 1 (Humans) examines if FKBP5 single nucleotide polymorphisms (SNPs) and PTSD symptom domains (re-experiencing, avoidance/numbing, hyperarousal) are associated with abnormal fear extinction phenotypes identified using latent growth mixture modeling (LGMM). Study 2 (Mice) tests if increasing doses of dexamethasone administered prior to extinction alters Fkbp5 mRNA production in the amygdala after extinction and recall and prevents the development of abnormal extinction phenotypes. In humans, abnormal extinction was associated with the 'IT homozygous genotype of FKBP5 SNPs RS9470080 and RS1360780, and hyperarousal symptoms. In mice, dexamethasone 300 mu g/kg was associated with increased amygdala Fkbp5 mRNA following extinction and robust extinction learning while lower doses were not associated with amygdala Fkbp5 mRNA or differences in extinction learning. Further, mice that extinguished on dexamethasone 300 mu g/kg maintained low levels of freezing behavior during recall training while mRNA levels were no longer elevated. Together, findings indicate that FKBP5 confers risk for fear extinction deficits. However, this risk may be ameliorated by increasing fkbp5 mRNA expression in the amygdala during memory consolidation making this mechanism a plausible point of acute intervention to prevent the development of PTSD. (C) 2016 Elsevier Ltd. All rights reserved.
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