Glucocorticoid control of gene transcription in neural tissue

Abstract

Glucocorticoid hormones exert modulatory effects on neural function in a delayed genomic fashion. The two receptor types that can bind glucocorticoids, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), are ligand-inducible transcription factors. Therefore, changes in gene expression most likely underlie glucocorticoid-mediated genomic effects on neural function. In this thesis, the central aim was to gain more insight into the transcriptional changes that mediate the effects of acutely activated GRs on neural function.

Two different biological substrates i.e. ex vivo hippocampal slices and neuronal catecholaminergic PC12 cells, were used to measure the transcriptional response after GR-activation. Using microarrays, an interesting time-dependent pattern of gene transcription was observed, shifting from exclusively downregulated genes 1 hour after GR-activation to both up and downregulated genes 3 hours afterwards. This pattern suggests that the fast genomic effects of glucocorticoids may be realized via transrepression, preceding a later wave of transactivation.

Additionally, many new candidate genes were found that could potentially underlie (part of) the effects glucocorticoids mediate on hippocampal and catecholaminergic neuronal function. Hence, these candidate genes can be used to formulate new hypotheses on how glucocorticoids affect neural function and future research should therefore focus on testing these hypotheses.