ReviewCentral corticosteroid actions: Search for gene targets
Introduction
While knowledge of the physiological consequences of corticosteroid action in the brain on cognition, behaviour and mood is increasing, the molecular mechanisms underlying central corticosteroid action are only just starting to be understood. Genomic effects of corticosteroids, resulting in modification of transcription of target genes, is most likely one of the main mechanisms underlying corticosteroid action in the brain. In the last decade large scale gene expression profiling has evolved as a powerful tool to assess corticosteroid-mediated transcriptional changes within the brain, driven by a clear interest in identifying new drug targets for stress-related brain disorders. However, translating the observed effects on gene expression into a clear cut understanding of corticosteroid action has so far proven to be difficult. In this review we give an overview of the current status of the field on identification of central corticosteroid targets, discuss the opportunities and pitfalls and highlight new developments in understanding central corticosteroid action.
Section snippets
Corticosteroid receptors in brain mediate both rapid and slow effects
The brain is a major target for corticosteroids, that readily enter the brain and bind to a binary receptor system consisting of glucocorticoid receptors and mineralocorticoid receptors. These two corticosteroid receptors not only differ in ligand affinity but also in distribution throughout the brain, resulting in a fine-tuning of the central response to these hormones depending on the subregional mineralocorticoid receptor/glucocorticoid receptor balance and circulating hormone levels. While
Genomic mode of action of corticosteroid receptors
Upon ligand-binding, both mineralocorticoid and glucocorticoid receptors translocate to the cell nucleus where they can modulate gene transcription via transactivation and transrepression (Beato and Sanchez-Pacheco, 1996) (Fig. 1). In transactivation, the ligand-bound receptor forms homodimers that bind to glucocorticoid response elements (GREs) on the DNA in the proximity of gene promoters. Subsequently, cofactors (coactivators and/or corepressors) and histone-modifying enzymes are recruited
Large-scale gene expression profiling to identify central corticosteroid targets
In the last decade the availability of powerful large-scale gene expression profiling technology, such as DNA microarrays (Lockhart et al., 1996) and Serial Analysis of Gene Expression (Velculescu et al., 1995) has revolutionised the field of genomics, allowing entire transcriptomes to be rapidly characterized in a quantitative manner. By profiling the expression levels of several thousands of genes, glucocorticoid-regulated genes can be identified, allowing new hypotheses to be generated as to
Mineralocorticoid receptor and glucocorticoid receptor-specificity of the genomic response
Despite the issues complicating expression profiling in the brain, several studies have attempted to identify central corticosteroid targets. A major focus has been on the hippocampus as an important target tissue of corticosteroids in the brain, expressing both mineralocorticoid and glucocorticoid receptors. A first relevant question is whether mineralocorticoid and glucocorticoid receptors have their own target genes? Unfortunately, this question still remains largely unaddressed. Although
The transcriptional response to acute glucocorticoid receptor activation is highly dynamic
A lot of our understanding of central corticosteroid effects comes from electrophysiological studies on hippocampal neurons (Joels et al., 1994, Karst and Joels, 1991, Karst et al., 2000). Electrical currents can be measured in hippocampal explant slice preparations for hours after removal from the animal. Using the identical set up to what is used in electrophysiological studies a time curve of gene expression in response to glucocorticoid receptor-activation was investigated, in order to try
Cellular and environmental context determines glucocorticoid-dependent transcriptional response
Activated glucocorticoid receptors have been shown to exert different effects in different tissues and neural substrates. For example, glucocorticoid receptor-activation in the hypothalamic paraventricular nucleus (PVN) inhibits CRH neurons whereas extrahypothalamic CRH neurons are stimulated by activated glucocorticoid receptors (De Kloet et al., 2005, Makino et al., 1995). Additionally, expression of the monoamine oxidase A (MAO-A) gene was found to be inhibited by activated glucocorticoid
Functional gene classes affected by glucocorticoids in neural tissue
One aspect that has become evident from genomics studies on glucocorticoid effects is that these hormones can modulate transcription of genes involved in a wide variety of different cellular processes. Despite their contextual action, there is some overlap in glucocorticoid target genes when comparing different tissues, in particular of genes controlled by glucocorticoid response elements. The main functional gene classes regulated by glucocorticoids in neural tissue will be discussed below.
Linking functional effects of glucocorticoids in brain to glucocorticoid-responsive gene classes
At the molecular level the pleiotropic effects of glucocorticoids on brain function are mediated via the transcriptional control these stress hormones exert on a wide variety of functional genes classes. Although many central glucocorticoid gene targets have been identified so far, it remains a challenge to link these observations to the functional effects of glucocortioids in the brain. Due to the contextual action of glucocorticoids, the subtle changes in gene transcription induced by
Concluding remarks and future prospects
Large-scale profiling of glucocorticoid-responsive genes in neural tissue has revealed some remarkable features of the genomic response. These studies have shed light on the nature of the individual genes and functional gene classes transcriptionally regulated by glucocorticoids, as well as provided new insights into the receptor- and context-specificity and dynamics of the genomic response in brain. The current challenge is to select potentially interesting candidate genes and to generate
Acknowledgements
This work was supported by the Netherlands Organisation for Scientific Research (NWO) grants 836.06.010 (MEERVOUD) to N.A. Datson, 016.036.381 (VIDI) to O.C. Meijer and 903-42-197 and by the European Commission grant QLRT-2001-02758 (EUPEAH). E.R. de Kloet is supported by the Royal Netherlands Academy of Arts and Sciences (KNAW).
References (171)
- et al.
The neuronal mineralocorticoid receptor as a mediator of glucocorticoid response
Neuron
(1988) - et al.
Making memories stick: cell-adhesion molecules in synaptic plasticity
Trends Cell Biol.
(2000) Neurotrophin-induced activation of casein kinase 2 in rat hippocampal slices
Neuroscience
(1998)- et al.
Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus
Neuroscience
(1994) - et al.
Import of the glucocorticoid receptor into rat liver mitochondria in vivo and in vitro
J. Steroid Biochem. Mol. Biol.
(1993) - et al.
Glucocorticoid repression of pro-opiomelanocortin gene transcription
J. Steroid Biochem.
(1989) - et al.
A neurotrophic model for stress-related mood disorders
Biol. Psychiatry
(2006) - et al.
The genomic structure of the human glucocorticoid receptor
J. Biol. Chem.
(1991) - et al.
A molecular framework for the actions of glucocorticoid hormones in the nervous system
Neuron
(1989) - et al.
The effect of chronic exposure to highly aggressive mice on hippocampal gene expression of non-aggressive subordinates
Brain Res.
(2006)