Emily Bensema

Background: Major depressive disorder (MDD) is a subclass of depression distinguished from normal feelings of transient sadness by a duration exceeding two weeks with five or more depressive symptoms (as denoted by the DSM-5), one of which must be either depressed mood or anhedonia (inability to feel pleasure).¹ Environmental stressors such as childhood trauma, have been shown to contribute to the development of depression and epigenetic changes are suggested to be a key mechanism behind this.² Epigenetics are modifications to DNA that can change gene expression, but not the underlying nucleotide sequence.³ Though the exact mechanism is not fully understood, epigenetics is likely a bridge connecting the experience of stress and development of depression.³ Epigenetic changes in stress-related genes, such as those responsible for glucocorticoid signaling, are promising for future therapies, but additional research is necessary as the directionality of these modifications is not well understood.⁴ One such gene is FKBP5, a co-chaperone of the glucocorticoid receptor complex within the hypothalamic pituitary axis (HPA). The HPA is key in controlling the stress response and is mediated by negative feedback from glucocorticoids, protecting the body from prolonged stress.⁵ Depressed individuals show higher levels of glucocorticoid receptors, correlated with higher levels of FKBP5.⁵ Due to its importance in the stress response within the HPA, FKBP5 was the gene of interest within this narrative review.⁵

Objective: The purpose of this review was to explore the mechanisms by which early life adversity contributes to developing MDD, mediated through the FKBP5 gene.

Search methods: A search in the PubMed database was conducted from 2018 to 2024 using the keywords: “epigenetics”, “major depressive disorder”, “adverse childhood events”.

Results: Studies show that Early Life Adversity (ELA) in the form of maternal separation contributes to changes in gene transcription and the risk of behavioral disorders later in life.⁴ Social interaction tests revealed altered sociability in ELA-exposed rats, with maternally separated groups preferring familiar conspecifics. Amygdala gene expression analysis showed elevated Dnmt3a9 and Tet3 levels in separated rats, indicating disrupted transcription pathways.⁴ DNA methylation changes were widespread in prenatal-enrichment exposed females, with sex-specific differences observed within the FKBP5 gene.⁶ A synergistic corticosterone reduction was observed in FKBP5-overexpressing mice exposed to maternal separation, particularly in females. ELA mitigated depressive symptoms in females but exacerbated them in males. ELA induced alterations in gene expression and increased anxiety-like behavior and depression susceptibility, while zebularine treatment normalized DNA methylation and improved behavior.³

Conclusion: The studies within this narrative review began to elicit the relationship between early life adversity, epigenetic changes of genes within the stress response, and development of MDD. These findings underscore the intricate relationship between early life experiences, gene expression, and behavior, highlighting the potential for targeted interventions such as zebularine to mitigate adverse effects.³ Through understanding the molecular mechanisms underlying these connections, we can provide insights into the long-term effects of early life stressors, assess trauma-related health risks, and utilize pharmacological interventions to target these epigenetic changes, reducing the impact of childhood trauma on the adult lives of patients.^3,4,5,6

Works Cited:

1. McCarron RM, Shapiro B, Rawles J, Luo J. Depression. Ann Intern Med. 2021;174(5):ITC65-ITC80. doi:10.7326/AITC202105180
2. Park C, Rosenblat JD, Brietzke E, et al. Stress, epigenetics and depression: A systematic review. Neuroscience & Biobehavioral Reviews. 2019;102:139-152. doi:10.1016/j.neubiorev.2019.04.010      Park, Neurosci Biobehav Rev (2019)
3. Keller SM, Doherty TS, Roth TL. Pharmacological Manipulation of DNA Methylation in Adult Female Rats Normalizes Behavioral Consequences of Early-Life Maltreatment. Front Behav Neurosci. 2018;12:126. doi:10.3389/fnbeh.2018.00126 Keller, Front Behav Neurosci (2018)
4. Karen C, Rajan KE. Social Behaviour and Epigenetic Status in Adolescent and Adult Rats: The Contribution of Early-Life Stressful Social Experience. Cell Mol Neurobiol. 2019;39(3):371-385. doi:10.1007/s10571-019-00655-x  Karen, Cell Mol Neurobiol (2019)
5. Ke X, Fu Q, Majnik A, Cohen S, Liu Q, Lane R. Adverse early life environment induces anxiety-like behavior and increases expression of FKBP5 mrna splice variants in mouse brain. Physiological Genomics. 2018;50(11):973-981. doi:10.1152/physiolgenomics.00054.2018  Ke, Physiol Genomics (2018)
6. Mattern F, Frahm J, Teschendorff AE, et al. Epigenetic programming by maternal enrichment and postnatal stress in the mouse. Behav Brain Res. 2019;359:143-148. doi:10.1016/j.bbr.2018.11.035 Mattern, Behav Brain Res (2019)