Expression of the PPM1F Gene Is Regulated by Stress and Associated with Anxiety and Depression
Open accessAbstract
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.
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Carrying the short allele of the 5-HTTLPR in high-stress environments increases depression risk.
“For example, carrying the short allele of the 5-HTTLPR in high-stress environments increases depression risk.”
From Comprehensive review of chronic stress pathways and the efficacy of behavioral stress reduction programs (BSRPs) in managing diseases. (2024) · cites this paper as [45]
Altered expression of the PPM1F gene in the amygdala and medial prefrontal cortex is linked to PTSD and depression.
“An altered expression of the PPM1F gene in the amygdala and medial prefrontal cortex (mPFC) is linked to PTSD and depression.”
From Comprehensive review of chronic stress pathways and the efficacy of behavioral stress reduction programs (BSRPs) in managing diseases. (2024) · cites this paper as [45]
Polymorphisms in the 5-HTTLPR gene correlate with cognitive dysfunction in PTSD-affected individuals.
“Similarly, polymorphisms in the 5-HTTLPR gene correlate with cognitive dysfunction in PTSD-affected individuals [33,45,48,49,50].”
From Comprehensive review of chronic stress pathways and the efficacy of behavioral stress reduction programs (BSRPs) in managing diseases. (2024) · cites this paper as [45]
Polymorphisms in genes such as EPHX2, OXTR, and NRG1 are associated with depression symptoms.
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From Comprehensive review of chronic stress pathways and the efficacy of behavioral stress reduction programs (BSRPs) in managing diseases. (2024) · cites this paper as [45]
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- Authors
- Wingo, A. P., Velasco, E. R., Florido, A., Lori, A., Choi, D. C., Jovanovic, T., Ressler, K. J., & Andero, R.
- Affiliations
- Emory University (US)
- Universitat Autònoma de Barcelona (ES)
- Georgia State University (US)
- Harvard University (US)
- Corresponding author
- Andero, Raül
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 83
- Issue
- 3
- Pages
- 284-295
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC5743606
- OpenAlex
- W2751936277
- Cited by
- 44
- References
- 47
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 6 · 2020: 6 · 2019: 4 · 2018: 2 · 2017: 1
- FWCI
- 1.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biological Psychiatry (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Ministerio de Economía y Competitividad
- National Alliance for Research on Schizophrenia and Depression (23419, 22434)
- Howard Hughes Medical Institute
- National Institutes of Health (R01MH096764, R01MH071537, R21MH101492-01, R01MH100122)
- U.S. Department of Veterans Affairs (IK2CX000601)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- post-traumatic stress disorder, depression, anxiety, restraint stress, traumatic stress, amygdala, medial prefrontal cortex, corticosterone, gene expression, transcriptome-wide analysis, sex differences, comorbidities
- MeSH terms
- Amygdala, Animals, Anxiety, Behavior, Animal, Depressive Disorder, Disease Models, Animal, Female, Male, Mice, Inbred C57BL, Phosphoprotein Phosphatases, Stress Disorders, Post-Traumatic, Stress, Psychological, Comorbidity, Prefrontal Cortex, Mice, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Transcriptome
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