Reduced Peripheral Expression of the Glucocorticoid Receptor α Isoform in Individuals with Posttraumatic Stress Disorder: A Cumulative Effect of Trauma Burden

Abstract

BackgroundPosttraumatic stress disorder (PTSD) is a serious psychiatric condition that was found to be associated with altered functioning of the hypothalamic-pituitary-adrenal (HPA) axis and changes in glucocorticoid (GC) responsiveness. The physiological actions of GCs are primarily mediated through GC receptors (GR) of which isoforms with different biological activities exist. This study aimed to investigate whether trauma-experience and/or PTSD are associated with altered expression of GR splice variants.MethodsGRα and GRβ mRNA expression levels were determined by real-time quantitative PCR in whole blood samples of individuals with chronic and severe forms of PTSD (n = 42) as well as in ethnically matched reference subjects (non-PTSD, n = 35).ResultsIndividuals suffering from PTSD exhibited significantly lower expression of the predominant and functionally active GRα isoform compared to non-PTSD subjects. This effect remained significant when accounting for gender, smoking, psychotropic medication or comorbid depression. Moreover, the GRα expression level was significantly negatively correlated with the number of traumatic event types experienced, both in the whole sample and within the PTSD patient group. Expression of the less abundant and non-ligand binding GRβ isoform was comparable between patient and reference groups.ConclusionsReduced expression of the functionally active GRα isoform in peripheral blood cells of individuals with PTSD seems to be a cumulative effect of trauma burden rather than a specific feature of PTSD since non-PTSD subjects with high trauma load showed an intermediate phenotype between PTSD patients and individuals with no or few traumatic experiences.

Glucocorticoid sensitivity and inflammatory status of peripheral blood mononuclear cells in patients with coronary artery disease

“…The mRNA levels of GR-b, as opposed to GR-a, were extremely low in both CAD patients and controls. This is in agreement with previous studies showing that GR-b mRNA levels in PBMCs are up to 2000 times lower than GR-a mRNA levels [33,34]. Upregulated levels of GR-b have been associated with glucocorticoid unresponsiveness in cell line models and glucocorticoid-resistant forms of diseases, such as asthma, rheumatoid arthritis and inflammatory bowel disease [12,[35][36][37].…”

Glucocorticoid receptor DNA methylation, childhood maltreatment and major depression

“…This notion is supported by a study reporting significantly decreased GRα mRNA expression in participants with PTSD compared to healthy controls. Of particular relevance to the current work is the finding that decreased GRα expression was modulated by a dose-response effect of trauma irrespective of PTSD status, such that those with higher trauma loads showed more marked decrease in GRα expression (Gola et al, 2014). …”

The effect of sex and irritable bowel syndrome on HPA axis response and peripheral glucocorticoid receptor expression

“…While expression of the inactive GRβ plays an important role in inflammatory disorders, expression of GRα has been associated with stress-related and psychiatric disorders. There are no other published studies of GR mRNA in IBS, but lower PBMC GRα mRNA was also found in association with fibromyalgia (Macedo et al, 2008), which has shared pathophysiology with IBS, and in post-traumatic stress disorder (Gola et al, 2014). Limited evidence for a link between peripheral and central GR expression exists (Hepgul et al, 2013).…”

“…(Johnson and Greenwood-Van Meerveld, 2015) In humans, decreased central expression of GRs has been associated with depression in findings from autopsy specimens, (Webster et al, 2002) and impaired negative feedback in depression is also supported by the consistent response to dexamethasone suppression or dexamethasone-CRF testing. Though negative feedback is mediated by GRs in the central nervous system, changes in peripheral blood mononuclear cell (PBMC) GR number, (de Kloet et al, 2007) sensitivity, (Yehuda et al, 2004) promoter methylation status, (Yehuda et al, 2015) and mRNA expression (Gola et al, 2014; Hepgul et al, 2013) have been reported in psychiatric disease associated with negative feedback of the HPA axis. While studies in IBS have not supported impaired negative feedback based on dexamethasone suppression, (Bohmelt et al, 2005; Dinan et al, 2006) PBMC GR mRNA expression has not been studied.…”