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Developmental regulation of the 5‐HT7 serotonin receptor and transcription factor NGFI‐A in the fetal guinea‐pig limbic system: influence of GCs

Fetal exposure to excess glucocorticoids (GCs) programs the developing hypothalamo–pituitary–adrenal (HPA) axis, and may predispose offspring to adult‐onset disease. During development, serotonin (5‐HT) influences transcription of hippocampal GR mRNA via the 5‐HT7 receptor. The effect of 5‐HT on GR involves the transcription factor NGFI‐A. Given the developmental changes which we have previously reported in hippocampal GR mRNA expression, we hypothesized that (1) there are progressive developmental changes in 5‐HT7 receptor and NGFI‐A mRNA expression in the fetal guinea‐pig limbic system, and (2) repeated exposure to synthetic GC treatment will significantly modify developmental expression of these genes. 5‐HT7 receptor mRNA was highly expressed in the hippocampus and thalamus at gestational day (gd) 40 (term ∼70 days), and significantly decreased (P < 0.05) with advancing gestation. Conversely, NGFI‐A mRNA expression in the hippocampus and frontal cortex was almost undetectable at gd40, but was dramatically elevated (P < 0.05; 8‐fold) near term. Changes in mRNA were refelected by NGFI‐A protein levels. These changes were significantly correlated to hippocampal GR expression and fetal plasma cortisol concentrations. Synthetic GC treatment increased NGFI‐A mRNA levels in CA1 and the cingulate cortex, but had no effect on 5‐HT7 receptor expression. In conclusion our results suggest that (1) limbic 5‐HT7 receptor expression is not directly linked to maturation of hippocampal GR in late gestation; (2) the up‐regulation of NGFI‐A expression near term is driven by glucocorticoid; and (3) premature exposure to synthetic glucocorticoid significantly increases NGFI‐A‐related transcriptional activity in the fetal limbic system.