Post-traumatic stress disorder (PTSD) can develop after a traumatic event, with its impacts originating at the subcellular level (Girgenti, et al., 2017; Yehuda and Seckl, 2011). The pathophysiology of PTSD at this scale is characterized by a disruption of glucocorticoid (GC) hormone signaling, which has implications for other cellular processes related to stress regulation.
Cortisol, the “stress hormone,” is the most notable GC in the pathophysiology of PTSD (Girgenti, et al., 2017). It is involved in consolidating and retrieving fearful memories and works to promote the body’s stress response (Binder, 2009). However, cortisol is also important in terminating this response via a negative feedback loop (Figure 1). Post-traumatic stress disorder has been observed to cause either hypercortisolism or (more commonly) hypocortisolism—a deficit of cortisol. This, however, is not due to dysfunction of the adrenal or pituitary glands, but involves this negative feedback loop (Yehuda and Seckl, 2011).
Hypocortisolism in those with PTSD is closely related to glucocorticoid receptors (GRs) (Girgenti, et al., 2017). GRs are transcription factors that move from the cytoplasm into the nucleus after GC binding and mediate the effect of cortisol (Binder, 2009). Post-traumatic stress disorder often causes supersensitivity to GRs, which combines with the deficiency of cortisol to impair the negative feedback loop.
The negative feedback loop regulates the hypothalamic-pituitary-adrenal axis, which coordinates the body’s hormonal response to stress (Mendonça, Mangiavacchi and Rios, 2021). This stress response is fundamental for maintaining homeostasis (via the feedback loop); similarly, the proper functioning of this negative feedback loop is vital for normal stress responses (Binder, 2009). As the subcellular effects of PTSD disrupt this feedback, it disrupts the body’s ability to carry out its natural stress response in a healthy manner.
The translocation and the action of glucocorticoid receptors on gene transcription is controlled by a molecular complex, the most significant part being the co-chaperone proteins that collaborate to transport molecules (Binder, 2009). The most notable of these is FK506-binding protein 5 (FKBP5), which binds to a GR and inhibits its translocation into the nucleus, and only detaches to allow this movement after cortisol binds to the GR (Girgenti, et al., 2017; Kang, et al., 2019). The transcription of FKBP5 (the gene that codes for FKBP5) is induced by the binding of the GR-GC complex to its promoter region (also known as a GRE) as part of the negative feedback loop (Figure 1) (Binder, 2009; Girgenti, et al., 2017).
Figure 1: A diagram showing the normal feedback loop (left) and the impacted feedback loop associated with PTSD (right). The normal feedback loop shows an adequate amount of cortisol, such that when less FKBP5 is present and the GR-GC binding tendency increases, there is sufficient cortisol to allow for the binding and subsequent translocation to bind to a GRE and activate transcription of FKBP5. In the impaired feedback loop, there is insufficient cortisol to allow for translocation of GR; therefore, the FKBP5 deficiency will not be countered and the stress response will become disrupted (Girgenti, et al., 2017).
FKBP5 expression has been found to be reduced in patients with PTSD, which is consistent with the noted higher GR sensitivity, as increased expression of the gene has been found to decrease GR sensitivity (Binder, 2009). Less FKBP5 present increases the tendency of GRs to bind to GCs; however, cortisol production is suppressed, so there is not enough cortisol present for all available GRs, which interrupts the feedback loop (Mendonça, Mangiavacchi and Rios, 2021). In addition, there will be fewer GR-GC complexes translocating into the nucleus to prompt FKBP5 transcription, exacerbating the deficiency of FKBP5 and further disrupting the feedback.
It is certainly disconcerting to think that such significant impacts to one’s life and psyche can be enforced by something so small and intangible as these molecules and processes. However, understanding the root of such disorders allows for the development of potential treatments and prevention mechanisms so that the impact is less devastating.
References
Binder, E.B., 2009. The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology, 34, pp.S186–S195. https://doi.org/10.1016/j.psyneuen.2009.05.021.
Girgenti, M.J., Hare, B.D., Ghosal, S. and Duman, R.S., 2017. Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD. Current Psychiatry Reports, 19(11), p.85. https://doi.org/10.1007/s11920-017-0841-3.
Kang, J.I., Kim, T.Y., Choi, J.H., So, H.S. and Kim, S.J., 2019. Allele-specific DNA methylation level of FKBP5 is associated with post-traumatic stress disorder. Psychoneuroendocrinology, 103, pp.1–7. https://doi.org/10.1016/j.psyneuen.2018.12.226.
Mendonça, M.S., Mangiavacchi, P.M. and Rios, Álvaro.F.L., 2021. Regulatory functions of FKBP5 intronic regions associated with psychiatric disorders. Journal of Psychiatric Research, 143, pp.1–8. https://doi.org/10.1016/j.jpsychires.2021.08.014.
Yehuda, R. and Seckl, J., 2011. Minireview: Stress-related psychiatric disorders with low cortisol levels: A Metabolic Hypothesis. Endocrinology, 152(12), pp.4496–4503. https://doi.org/10.1210/en.2011-1218.