Gluco‐ and mineralocorticoid receptor‐mediated regulation of neurotrophic factor gene expression in the dorsal hippocampus and the neocortex of the rat

Abstract

Gluco- and mineralocorticoid receptors (GR and MR) act via common promoter elements but may exert different effects on gene regulation in various regions of the forebrain. In order to separately analyse the role of GR and MR in the regulation of neurotrophic factor genes and their receptors, we used adrenalectomy and subsequent hormone injections in the rat as a model system. Twenty-four hours after adrenalectomy rats were injected with a single dose of corticosterone (2 and 10 mg/kg), aldosterone (0.5 mg/kg) or the synthetic glucocorticoid agonist RU 28362 (4 mg/kg). Gene expression of basic fibroblast growth factor (bFGF) and its high-affinity receptors [fibroblast growth factor receptor subtypes 1-3 (FGF-R1, FGF-R2, FGF-R3)], as well as brain-derived growth factor (BDNF) and neurotrophin-3 (NT-3) was analysed at 4 h after the hormone injection in CA1-CA4 (cornus of Ammon areas of the hippocampus) and dentate gyrus of the dorsal hippocampus and in neocortex by means of in situ hybridization. We found that bFGF is regulated in CA2, CA3 and dentate gyrus by GR and MR together, and in CA1, CA4 and neocortex by GR alone. FGF-R2 expression in the hippocampus seems to be regulated only by MR, while BDNF expression appears to depend on both receptors. FGF-R1, FGF-R3 and NT-3 were only moderately affected by the hormone activation of GR and MR acting in concert or alone in the various regions. Thus, the present findings suggest that the adrenal cortical system through GR and MR participate in the control of neurotrophic factor signalling in a highly subregion- and cellular-dependent manner.

Time-course of immediate early gene expression in hippocampal subregions of adrenalectomized rats after acute corticosterone challenge

“…However, we have no evidence for the view that these supramaximal doses produce antagonistic effects in the present model. Thus, in a previous paper (Hansson et al, 2000) it was found that in the present adrenalectomized model a low dose (2 mg/kg, giving similar levels to nadir) and a high dose of corticosterone (10 mg/kg) give a similar rise of bFGF mRNA levels in the dorsal hipopocampus and a similar reduction of BDNF mRNA levels in this region. Thus, a full saturation and activation of intracellular GR and MR (Reul et al, 1987a;Reul et al, 1987b) likely occurs after treatment with this dose of CORT in this time period; by comparison, the plasma levels at the 8 h time point are similar to those as seen at nadir in normal and untreated rats, and may lead most likely to predominant MR activation, but also to some GR activation (Sapolsky et al, 1986;Spencer et al, 1991).…”

“…Subsequent treatment with low and high doses of CORT hormone allowed us to separately analyze the consequences of GR and MR activation on gene expression profiles without interference from endogenous adrenocorticosteroid hormones potentially preoccupying GR and MR (Hansson et Hansson and Fuxe, 2002). In a previous paper we established that in the present acutely adrenalectomized rat model there exists an upregulation of GR and MR mRNA levels in the dorsal hippocampus (Hansson et al, 2000). In the study presented here, a high dose of CORT (10 mg/kg, s.c.) was chosen in order to fully activate both GR and MR over several hours (Hansson et al, 2003;Hansson and Fuxe, 2002).…”

From Acquisition to Consolidation: On the Role of Brain-Derived Neurotrophic Factor Signaling in Hippocampal-Dependent Learning

“…Furthermore, BDNF expression is modulated in the hippocampus by a variety of neurotransmitter and neuromodulatory systems, all of which have been implicated in hippocampal-dependent learning. Hippocampal BDNF expression is regulated by cholinergic (da Penha Berzaghi et al 1993;Lapchak et al 1993;Knipper et al 1994;French et al 1999), serotonergic (Nibuya et al 1995;Vaidya et al 1997Vaidya et al , 1999, and nitric oxide (Xiong et al 1999) manipulations, as well as by both gluco-and mineralocorticoids (Schaaf et al 1998;Hansson et al 2000). In addition to these in vitro manipulations, and more relevant to learning and memory, BDNF expression is also regulated in vivo by various environmental interactions.…”

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

“…6,11,16 GR has a critical role in normal human brain development 17 and controls the transcription of a range of genes critical to psychiatric health. 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.…”