title: A cross species study of heterogeneity in fear extinction learning in relation to FKBP5 variation and expression: Implications for the acute treatment of posttraumatic stress disorder.
abstract: 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 TT homozygous genotype of FKBP5 SNPs RS9470080 and RS1360780, and hyperarousal symptoms. In mice, dexamethasone 300 μg/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 μg/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.
authors.affiliation: NYU School of Medicine, United States; Steven and Alexandra Cohen Veterans Center for Post Traumatic Stress and Traumatic Brain Injury, United States. Electronic address: Isaac.Galatzer-Levy@nyumc.org.
authors.forename: Isaac R
authors.initials: IR
authors.lastname: Galatzer-Levy
authors.affiliation: Universitat Autònoma de Barcelona, Spain; McLean Hospital, United States; Harvard University, United States.
authors.forename: Raül
authors.initials: R
authors.lastname: Andero
authors.affiliation: Maritime Self-Defense Force, Japan.
authors.forename: Takehito
authors.initials: T
authors.lastname: Sawamura
authors.affiliation: Emory University School of Medicine, United States; Atlanta VA Medical Center, United States.
authors.forename: Tanja
authors.initials: T
authors.lastname: Jovanovic
authors.affiliation: University of Texas Austin, United States.
authors.forename: Santiago
authors.initials: S
authors.lastname: Papini
authors.affiliation: McLean Hospital, United States; Harvard University, United States.
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Ressler
authors.affiliation: Emory University School of Medicine, United States; Atlanta VA Medical Center, United States.
authors.forename: Seth Davin
authors.initials: SD
authors.lastname: Norrholm
mesh_terms: D000328:Adult; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001143:Arousal / Q000187:drug effects / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D008297:Male; D011939:Mental Recall / Q000187:drug effects / Q000502:physiology; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D013216:Reflex, Startle / Q000502:physiology; D013313:Stress Disorders, Post-Traumatic / Q000235:genetics* / Q000378:metabolism* / Q000523:psychology; D022021:Tacrolimus Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D000099159:Tacrolimus Binding Protein 5
chemical_list: D003907:Dexamethasone; D005938:Glucocorticoids; D012333:RNA, Messenger; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5
keywords: Dexamethasone; FKBP5; Fear extinction; Latent growth mixture modeling; Posttraumatic stress; Resilience; Threat extinction; Translational model; mRNA