Ontogeny of hippocampal corticosteroid receptors: Effects of antenatal glucocorticoids in human and mouse

Abstract

Women at risk for preterm delivery are treated with synthetic glucocorticoids (GCs) to enhance fetal lung maturation. GCs can bind to two intracellular receptors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), which function as transcription factors. Both are highly expressed in the hippocampus. Several studies have focused on adverse side effects of antenatal GC treatment. However, relatively little is known about the ontogeny of GR and MR, especially in human. Therefore, we studied the ontogeny of both receptors in the human and mouse hippocampus and investigated the effects of antenatal dexamethasone (dex) treatment, a synthetic glucocorticoid, on MR and GR mRNA levels during hippocampal development. The results demonstrate that MR mRNA was first expressed in mouse hippocampus at embryonic day (E)15.5, at the timepoint when dex was administered. In contrast, GR mRNA expression was first observed after birth at postnatal day (P)5. However, in the human hippocampus both receptors are expressed at 24 weeks of gestation, when antenatal GCs are administered in clinical practice. Quantitative in situ hybridization demonstrated that MR mRNA levels were reduced only shortly after dex treatment at E16, but were unaffected from E18 onwards. These findings indicate that a single antenatal dex administration at E15.5 transiently affects MR mRNA levels in the mouse hippocampus. No effect of antenatal dex treatment was found on the human hippocampus at the third trimester of pregnancy. These data on the prenatal ontogeny of both corticosteroid receptors in the human hippocampus is important for understanding the significance of fetal glucocorticoid or stress exposure and its potential effects on health and disease.

Exposure to Prenatal Psychobiological Stress Exerts Programming Influences on the Mother and Her Fetus

“…As mentioned above, fetal exposure to maternal cortisol is regulated by 11β-HSD2, but this placental enzyme is only a partial barrier so that a proportion of maternal cortisol passes through the placenta [105,106]. Glucocorticoid receptors are present throughout the CNS [107,108,109,110] and glucocorticoids easily pass through the blood-brain barrier [111] and influence multiple brain regions, including, but not limited to, the hippocampus, amygdala and prefrontal cortex. At high concentrations, cortisol may inhibit growth and differentiation of the developing nervous system; considerable evidence indicates that glucocorticoids are neurotoxic to hippocampal CA3 pyramidal cells [112,113,114].…”

Maternal influences on epigenetic programming of the developing hypothalamic‐pituitary‐adrenal axis

“…The ontogenic timing of hippocampal GR and MR expression is species-specific (Cintra et al, 1993;Diaz et al, 1998;Noorlander et al, 2006), suggesting that windows for glucocorticoid programming differ between species. Prenatal DEX exposure decreases GR and MR expression in the adult hippocampus, which may limit negative feedback and result in increased basal CORT levels in the adult (Levitt et al, 1996).…”

Corticoides antenatales y prevención del distrés respiratorio del recién nacido prematuro: utilidad de la terapia de rescate

“…Los potenciales efectos secundarios de la administración de corticoides antenatales incluyen alteraciones del desarrollo cerebral y del eje hipotálamo-hipófisis-suprarrenal del feto, con posible repercusión a nivel cognitivo de comportamiento, y sobre las respuestas cardiovasculares, inmune y de adaptación al estrés, riesgos que se verían aumentados con la administración de dosis repetidas 14,15 . Sin embargo, distintos trabajos han realizado un seguimiento hasta los 6 años de edad de RNPT expuestos antenatalmente a ciclos repetidos de corticoides, y las habilidades cognitivas de estos pacientes no difieren de los expuestos a placebo 16---19 .…”