Distinct Ontogeny of Glucocorticoid and Mineralocorticoid Receptor and 11β-Hydroxysteroid Dehydrogenase Types I and II mRNAs in the Fetal Rat Brain Suggest a Complex Control of Glucocorticoid Actions

Abstract

Glucocorticoids (GCs) act via intracellular mineralocorticoid (MR) and glucocorticoid receptors (GR). However, it has recently been recognized that GC access to receptors is determined by the presence of tissue-specific 11β-hydroxysteroid dehydrogenases (11β-HSDs) that catalyze the interconversion of active corticosterone and inert 11-dehydrocorticosterone. 11β-HSD type 1 (11β-HSD1) is a bidirectional enzymein vitrothat acts predominantly as a reductase (regenerating corticosterone) in intact neurons. In contrast, 11β-HSD type 2 (11β-HSD2) is a higher affinity exclusive dehydrogenase that excludes GCs from MR in the kidney, producing aldosterone-selectivityin vivo. We have examined the ontogeny of 11β-HSD mRNAs and enzyme activity during prenatal brain development and correlated this with GR and MR mRNA development. These data reveal that (1) 11β-HSD2 mRNA is highly expressed in all CNS regions during midgestation, but expression is dramatically reduced during the third trimester except in the thalamus and cerebellum; (2) 11β-HSD2-like activity parallels closely the pattern of mRNA expression; (3) 11β-HSD1 mRNA is absent from the CNS until the the third trimester, and activity is low or undectectable; and (4) GR mRNA is highly expressed throughout the brain from midgestation, but MR gene expression is absent until the last few days of gestation. High 11β-HSD2 at midgestation may protect the developing brain from activation of GR by GCs. Late in gestation, repression of 11β-HSD2 gene expression may allow increasing GC activation of GR and MR, permitting key GC-dependent neuronal and glial maturational events.

Enhanced Hippocampal Long-Term Potentiation and Spatial Learning in Aged 11β-Hydroxysteroid Dehydrogenase Type 1 Knock-Out Mice

“…This might have longlasting effects on hippocampal function because prenatal stress reduces hippocampal neurogenesis to old age (Lemaire et al, 2000). Although 11␤-HSD1 is little expressed in the hippocampus until birth (Diaz et al, 1998), it is highly expressed postnatally (Moisan et al, 1992) and it is therefore conceivable that 11␤-HSD1 deficiency associates with increased neurogenesis from early postnatal life. However, both genotypes showed markedly reduced newborn cell proliferation with age in the subgranular zone of the dentate gyrus, consistent with previous reports (Cameron and McKay, 1999;Heine et al, 2004), although the total number of newborn cells in aged 11␤-HSD1 Ϫ/Ϫ mice tended to be greater than aged controls.…”

Extensive Reorganization of Primary Afferent Projections into the Gustatory Brainstem Induced by Feeding a Sodium-Restricted Diet during Development: Less Is More

“…For example, maternal undernutrition reduces fetal levels of 11␤-hydroxysteriod dehydrogenase type 2, which is present in the fetal rat medulla during our dietary manipulation (Diaz et al, 1998). A decrease in this enzyme causes an increase in maternal glucocorticoid levels (Fleming et al, 2004;Owen et al, 2005), leaving the fetus vulnerable to the effects of excess maternal glucocorticoids (Fleming et al, 2004;Fujioka et al, 2006).…”

The Size and Distribution of Midbrain Dopaminergic Populations are Permanently Altered by Perinatal Glucocorticoid Exposure in a Sex- Region- and Time-Specific Manner

“…The multi-drug resistance gene product, P-glycoprotein, that extrudes all but 5-10% of circulating dexamethasone from the adult brain has not been detected in the rat before P7 (Matsuoka et al, 1999). Additionally, GRs are expressed in the basal ganglia from E15.5 in the rat (Diaz et al, 1998). It is therefore feasible that dexamethasone may exert its actions directly in the developing brain.…”