Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor

被引:579
作者
Ressler, Kerry J. [1 ,2 ,4 ]
Mercer, Kristina B. [1 ]
Bradley, Bekh [2 ,3 ]
Jovanovic, Tanja [2 ]
Mahan, Amy [4 ]
Kerley, Kimberly [1 ]
Norrholm, Seth D. [2 ,3 ]
Kilaru, Varun [2 ]
Smith, Alicia K. [2 ]
Myers, Amanda J. [5 ]
Ramirez, Manuel [5 ]
Engel, Anzhelika [5 ]
Hammack, Sayamwong E. [6 ]
Toufexis, Donna [4 ,6 ]
Braas, Karen M. [7 ,8 ]
Binder, Elisabeth B. [2 ,9 ]
May, Victor [7 ,8 ]
机构
[1] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA
[2] Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA
[3] Atlanta VA Med Ctr, Atlanta, GA 30033 USA
[4] Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA
[5] Univ Miami, Miller Sch Med, Miami, FL 33136 USA
[6] Univ Vermont, Dept Psychol, Burlington, VT 05401 USA
[7] Univ Vermont, Coll Med, Dept Anat & Neurobiol, Burlington, VT 05401 USA
[8] Univ Vermont, Coll Med, Dept Pharmacol, Burlington, VT 05401 USA
[9] Max Planck Inst Psychiat, D-80804 Munich, Germany
关键词
CYCLASE-ACTIVATING POLYPEPTIDE; ADENYLATE-CYCLASE; SIGNAL-TRANSDUCTION; BRAIN-DEVELOPMENT; STRIA TERMINALIS; GENE-EXPRESSION; FEAR INHIBITION; BED NUCLEUS; AMYGDALA; PTSD;
D O I
10.1038/nature09856
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. In contrast, it is unclear if the PACAP-PAC1 receptor pathway has a role in human psychological stress responses, such as post-traumatic stress disorder (PTSD). Here we find, in heavily traumatized subjects, a sex-specific association of PACAP blood levels with fear physiology, PTSD diagnosis and symptoms in females. We examined 44 single nucleotide polymorphisms (SNPs) spanning the PACAP (encoded by ADCYAP1) and PAC1 (encoded by ADCYAP1R1) genes, demonstrating a sex-specific association with PTSD. A single SNP in a putative oestrogen response element within ADCYAP1R1, rs2267735, predicts PTSD diagnosis and symptoms in females only. This SNP also associates with fear discrimination and with ADCYAP1R1 messenger RNA expression in human brain. Methylation of ADCYAP1R1 in peripheral blood is also associated with PTSD. Complementing these human data, ADCYAP1R1 mRNA is induced with fear conditioning or oestrogen replacement in rodent models. These data suggest that perturbations in the PACAP-PAC1 pathway are involved in abnormal stress responses underlying PTSD. These sex-specific effects may occur via oestrogen regulation of ADCYAP1R1. PACAP levels and ADCYAP1R1 SNPs may serve as useful biomarkers to further our mechanistic understanding of PTSD.
引用
收藏
页码:492 / 497
页数:6
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