Acute Activation of Hippocampal Glucocorticoid Receptors Results in Different Waves of Gene Expression Throughout Time

Abstract

Several aspects of hippocampal cell function are influenced by adrenal-secreted glucocorticoids in a delayed, genomic fashion. Previously, we used Serial Analysis of Gene Expression to identify glucocorticoid receptor (GR)-induced transcriptional changes in the hippocampus at a fixed time point. However, because changes in mRNA levels are transient and most likely precede the effects on hippocampal cell function, the aim of the current study was to assess the transcriptional changes in a broader time window by generating a time curve of GR-mediated gene expression changes. Therefore, we used rat hippocampal slices obtained from adrenalectomised rats, substituted in vivo with low corticosterone pellets, predominantly occupying the hippocampal mineralocorticoid receptors. To activate GR, slices were treated in vitro with a high (100 nM) dose of corticosterone and gene expression was profiled 1, 3 and 5 h after GR-activation. Using Affymetrix GeneChips, a striking pattern with different waves of gene expression was observed, shifting from exclusively down-regulated genes 1 h after GR-activation to both up and down regulated genes 3 h after GR-activation. After 5 h, the response was almost back to baseline. Additionally, real-time quantitative polymerase chain reaction was used for validation of a selection of responsive genes including genes involved in neurotransmission and synaptic plasticity such as the corticotropin releasing hormone receptor 1, monoamine oxidase A, LIMK1 and calmodulin 2. This permitted confirmation of GR-responsiveness of 15 out of 18 selected genes. In conclusion, direct activation of GR in hippocampal slices results in transient changes in gene expression. The pattern in which gene expression was modulated suggests that the fast genomic effects of glucocorticoids may be realised via transrepression, preceding a later wave of transactivation. Furthermore, we identified a number of interesting candidate genes which may underlie the glucocorticoid-mediated effects on hippocampal cell function.

Stress-induced changes in primate prefrontal profiles of gene expression

“…Exogenous glucocorticoids likewise downregulate the majority of glucocorticoid responsive genes in rodent hippocampus. 8,55,56 In monkey ventromedial prefrontal cortex, a subset of related genes differentially expressed after exposure to adult social stress was reliably identified in dChip and RMA data. These genes are ubiquitin conjugation enzymes (UBE2A, UBE2D2, UBE2E1) and ligases (SMURF2, UBR2, UBE3A) that target ubiquitin to protein substrates for selective degradation by the proteasome.…”

“…[1][2][3][4][5] Receptors for cortisol are densely expressed in prefrontal cortex 6,7 where they function as transcription factors that regulate gene expression. [8][9][10] Hundreds of genes in prefrontal cortex appear to be differentially expressed in humans with a history of major depression based on postmortem analysis of whole-genome microarray data. [11][12][13][14] These findings offer potential new insights for the discovery of stress-related genes involved in the pathophysiology of depression, 15,16 but must be considered with caution.…”

Corticosterone time-dependently modulates β-adrenergic effects on long-term potentiation in the hippocampal dentate gyrus

“…An interval of 2 h was chosen to ensure that gene-mediated effects can take place Wiegert et al 2005;Morsink et al 2006). Contrary to what was seen with isoproterenol only or with concurrent perfusion of both hormones, isoproterenol did not affect synaptic responses after TBS if corticosterone was applied to the same slice a few hours earlier.…”

Dynamic molecular and anatomical changes in the glucocorticoid receptor in human cortical development

“…23,24 The involvement of GR in modulating neurotransmitter availability through downregulation of monoamine oxidase A, which catabolizes dopamine, serotonin and noradrenaline and has been implicated in psychiatric illness, 25,26 has also been suggested. 22 Finally, GR downregulates the expression of GAP-43, 27 a mediator of synaptic plasticity, which is decreased in schizophrenia and bipolar disorder, 28,29 altered by maternal deprivation 30 and upregulated by antidepressants. 31 GR abnormalities and dysfunction of the HPA axis have been implicated in mental illness.…”

“…Brainderived neurotrophic factor, for example, has been shown to be downregulated by GR [18][19][20] as well as in schizophrenia. 21 Parvalbumin, a calcium-binding protein used as a marker of interneuron development, is upregulated by GR 22 and altered in schizophrenia. 23,24 The involvement of GR in modulating neurotransmitter availability through downregulation of monoamine oxidase A, which catabolizes dopamine, serotonin and noradrenaline and has been implicated in psychiatric illness, 25,26 has also been suggested.…”