Corticosteroids Modify Gene Expression

There are two endogenous receptors for CORT that are colocalized in several limbic brain structures such as the hippocampus and amygdala. The mineralocor- ticoid receptor (MR), which is expressed at high levels in the hippocampus, has a high affinity for its ligand and is already occupied under basal concentrations. The glucocorticoid receptor (GR) is ubiquitously expressed, has a tenfold lower affinity, and becomes occupied during rising concentrations of corticosteroids, for instance, during stress.

Both MR and GR belong to the superfamily of ligand-regulated nuclear receptors and are able to modify gene expression via two different mechanisms: (1) transactivation, in which the receptors bind to glucocorticoid-responsive elements (GREs) on the DNA and influence the transcription rate of the target genes, and (2) transrepression, in which the receptors interact with other transcription factors (such as activator protein-1 [AP-1] and nuclear factor-kß [NF-kß]), thereby inhibiting their transcriptional actions (Figure 1).

Figure 1. Molecular mechanisms of GR action on gene expression. Transactivation: after binding to corticosteroids, GRs translocate from the cytoplasm to the cell nucleus and bind to glucocorticoid-responsive elements (GREs) on the DNA, thereby influencing the transcription rates of target genes. Transrepression: corticosteroid-activated GRs bind to other transcription factors (such as AP-1), inhibiting their transcriptional actions

Effects of Stress on the Hippocampus. One of the major targets in the brain is the hippocampus, a structure that plays a crucial role in learning, memory, emotion, and regulation of the stress system. Several aspects of hippocampal cell function, such as neurotransmission and energy metabolism, are under the tight control of corticosteroids.

MR and GR, which are colocalized in hippocampal neurons, exert differential effects on hippocampal cell function. For instance, under low, basal concentrations in which only MR is occupied, neuroexcitability in hippocampal neurons is high, whereas under stress conditions, in which both MR and GR are occupied, neuroexcitability is low.

Thus, MR is involved in maintenance of neuronal excitability and basal activity of the stress system, while GR activation results in reduced hippocampal output and is involved in negative feedback to restore homeostasis. Inadequate corticosteroid input as well as chronic occupation of GR results in degeneration of hippocampal neuronal circuits, accompanied by deficits in cognition and maladaptation to stress. A balanced activation of MR/GR is therefore an important determinant of neuronal excitability, stress responsiveness, and neuronal health.

Since (1) MR and GR are able to modify gene expression and (2) the majority of the effects of corticosteroids on hippocampal cell function develop in a delayed manner, it can be hypothesized that changes in gene expression underlie these CORT-induced effects.

Therefore, by determining the CORT- induced changes in gene expression, the molecular mechanisms responsible for the actions of corticosteroids can be investigated. This entails measuring the expression levels of thousands of genes simultaneously, known as large-scale expression profiling, transcriptome analysis, or pharmacogenomics.