Effects of antenatal dexamethasone treatment on glucocorticoid receptor and calcyon gene expression in the prefrontal cortex of neonatal and adult common marmoset monkeys

Rochellys Diaz Heijtz,Hans Forssberg,Christopher R Pryce,Eberhard Fuchs,Joram Feldon

doi:10.1186/1744-9081-6-18

Abstract

BackgroundSynthetic glucocorticoids such as dexamethasone (DEX) are commonly used to promote fetal lung maturation in at-risk preterm births, but there is emerging evidence of subsequent neurobehavioral abnormalities in these children e.g. problems with inattention/hyperactivity. However, molecular pathways mediating effects of glucocorticoid overexposure on motor and cognitive development are poorly understood.MethodsIn this study with common marmoset monkeys, we investigated for neonatal and adulthood effects of antenatal DEX treatment on the expression of the corticosteroid receptors and also calcyon, a risk gene for attention-deficit/hyperactivity disorder, in the prefrontal cortex (PFC). Pregnant marmosets were exposed to DEX (5 mg/kg body weight) or vehicle during early (days 42-48) or late (days 90-96) stages of the 144-day pregnancy.ResultsIn neonates, relative to controls, glucocorticoid receptor (GR) mRNA levels were significantly reduced after the late DEX treatment in the medial, orbital and dorsal PFC and after the early DEX treatment in the dorsal PFC. The early DEX exposure, specifically, resulted in significant reduction in calcyon mRNA expression in the medial, orbital, dorsal and lateral PFC relative to controls. Mineralocorticoid receptor (MR) mRNA levels were not significantly affected by DEX treatment. In adults, PFC GR, calcyon, and MR mRNA levels were not significantly affected by early or late prenatal DEX treatment.ConclusionThese findings indicate that antenatal DEX treatment could lead to short-term alterations in PFC expression of the GR and calcyon genes, with possible neurodevelopmental functional consequences.

Highlights

Synthetic glucocorticoids such as dexamethasone (DEX) are commonly used to promote fetal lung maturation in at-risk preterm births, but there is emerging evidence of subsequent neurobehavioral abnormalities in these children e.g. problems with inattention/hyperactivity
Subsequent analysis showed that glucocorticoid receptor (GR) mRNA (Figs. 3A and 4) was significantly affected by prenatal DEX treatment in the medial (F(2,15) = 28.3, P < 0.001), orbital (F(2,15) = 8.2, P = 0.004), and dorsal (F(2,15) = 7.7, P = 0.005) prefrontal cortex (PFC)
Post-hoc analysis showed that LDEX neonates expressed significantly (P < 0.05) lower levels of GR mRNA in the medial and orbital PFC when compared to VEH neonates

Summary

Introduction

Synthetic glucocorticoids such as dexamethasone (DEX) are commonly used to promote fetal lung maturation in at-risk preterm births, but there is emerging evidence of subsequent neurobehavioral abnormalities in these children e.g. problems with inattention/hyperactivity. Epidemiological studies indicate that children exposed to elevated levels of glucocorticoids during fetal life because of maternal stress during pregnancy have an increased risk of developing hyperactivity and cognitive deficits, e.g., attention-deficit/hyperactivity disorder (ADHD) [1,2]. In spite of this potential risk, synthetic glucocorticoids such as dexamethasone (DEX) and betamethasone are widely used during pregnancy to prevent respiratory distress syndrome in preterm infants. Gene linkage and association studies have implicated the region of chromosome 10q, which contains the calcyon locus, with both the hyperactive/impulsive and inattentive symptoms of ADHD [9,10]. The PFC is involved in mediating numerous cognitive-executive functions, e.g. working memory, decision-making, inhibitory response control, and attentional set-shifting, of central relevance to ADHD [16]

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