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
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
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DOI：
10.1016/j.neuropharm.2016.12.023
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发表时间：
2017-04-01
影响因子：
4.7
通讯作者：
Norrholm, Seth Davin
中科院分区：
文献类型：
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作者：
Galatzer-Levy, Isaac R.;Andero, Raul;Norrholm, Seth Davin
恐惧消退学习的缺陷被假设为创伤后应激障碍（PTSD）发展的基础。这种缺陷可能部分是由于应激相关基因FKBP5的遗传和表观遗传变异。相反，在记忆巩固过程中改变FKBP5的表观遗传反应可能会挽救灭绝缺陷，使其成为急性干预的目标，以防止PTSD的发展。研究1（人类）研究了FKBP5单核苷酸多态性（snp）和创伤后应激障碍症状域（重新体验、逃避/麻木、过度觉醒）是否与使用潜在生长混合物模型（LGMM）确定的异常恐惧消退表型相关。研究2（小鼠）测试在灭绝前增加地塞米松剂量是否会改变灭绝和回忆后杏仁核中Fkbp5 mRNA的产生，并防止异常灭绝表型的发展。在人类中，异常灭绝与FKBP5 snp RS9470080和RS1360780的IT纯合基因型以及高唤醒症状相关。在小鼠中，300 μ g/kg地塞米松与消失后杏仁核Fkbp5 mRNA的增加和强大的消失学习有关，而低剂量地塞米松与杏仁核Fkbp5 mRNA或消失学习的差异无关。此外，地塞米松剂量为300 μ g/kg的小鼠在回忆训练中保持低水平的冻结行为，mRNA水平不再升高。总之，研究结果表明FKBP5具有恐惧灭绝缺陷的风险。然而，这种风险可能通过在记忆巩固过程中增加杏仁核中fkbp5 mRNA的表达来改善，这使得这种机制成为防止PTSD发展的急性干预的一个合理点。(C) 2016 Elsevier Ltd.版权所有。
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.