Expression of the PPM1F Gene Is Regulated by Stress and Associated With Anxiety and Depression

• Type of Material: Article
• Authors: Aliza Wingo, Emory University; Eric R. Velasco, Universitat Autonoma de Barcelona; Antonio Florido, Universitat Autonoma de Barcelona; Adriana Lori, Emory University; Dennis C. Choi, Georgia State University; Tanja Jovanovic, Emory University; Kerry Ressler, Emory University; Raul Andero, Universitat Autonoma de Barcelona
• Language: English
• Date: 2018-02-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Society of Biological Psychiatry
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.biopsych.2017.08.013
• Title of Journal or Parent Work: Biological Psychiatry
• ISSN: 0006-3223
• Volume: 83
• Issue: 3
• Start Page: 284
• End Page: 295
• Grant/Funding Information: TJ has support from NARSAD and R01MH100122.; APW was supported by the Department of Veterans Affairs Career Development Award IK2CX000601.; KJR received support from the Howard Hughes Medical Institute, RA and KJR were supported by R21MH101492-01, KJR by R01MH071537 and R01MH096764, and RA by a NARSAD Young Investigator Grant (22434), Ramon y Cajal RYC-2014-15784 MINECO and SAF2016-76565-R MINECO and FEDER.; The UAB Animal Facility received funding from 2015 FEDER7S-20IU16-001945.
• Keywords: PPM1F; Science & Technology; Neurosciences; AMYGDALA; CAMKII; Life Sciences & Biomedicine; CAMK2; 5-HT1A RECEPTORS; Depression; CORONARY-HEART-DISEASE; DISORDER SYMPTOMS; Psychiatry; PROTEIN-KINASE-II; Neurosciences & Neurology; POSTTRAUMATIC-STRESS; PREFRONTAL CORTEX; EXPOSURE; Anxiety; PTSD; Stress; PHOSPHATASE
• Research Categories: Psychology, Clinical; Biology, Genetics; Biology, Neuroscience

Abstract

Background Molecular mechanisms underlying psychological sequelae of exposure to stressful experiences, such as posttraumatic stress disorder (PTSD) and depression, are not well understood. Methods Using convergent evidence from animal and human transcriptomic and genomic studies, we aimed to identify genetic mechanisms underlying depression and anxiety after traumatic experiences. Results From a transcriptome-wide analysis in mice, we found the Ppm1f gene to be differentially expressed in the amygdala and medial prefrontal cortex (mPFC) a week after immobilization stress. Next, we found that PPM1F messenger RNA levels in human blood were downregulated in cases with symptoms of comorbid PTSD and depression and consistently in cases with anxiety symptoms in a separate human dataset. Furthermore, we showed that a genetic variant of PPM1F, rs17759843, was associated with comorbid PTSD and depression and with PPM1F expression in both human brain and blood. Given prior reported mechanistic links between PPM1F and CAMK2 (CAMKII), we examined blood messenger RNA level of CAMK2G in humans and found it to be lower in cases with comorbid PTSD and depression. We also found that PPM1F protein levels and colocalization with CAMK2G were altered in amygdala and mPFC of male mice. Additionally, we found that a systemic dose of corticosterone blocked the depressive-like phenotype elicited by stress in female mice. Lastly, corticosterone rescued the anxiety-like phenotype and messenger RNA levels of Ppm1f in amygdala and mPFC in male mice and in mPFC of female mice. Conclusions Taken together, our data suggest a mechanistic pathway involving PPM1F and CAMK2G in stress- and trauma-related manifestation of anxiety and depression across species.