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 approximately 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.
Andrews
Marcus H
MH
Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S1A8, Canada. m.andrews@utoronto.ca
Kostaki
Alice
A
Setiawan
Elaine
E
McCabe
Lucy
L
Owen
Dawn
D
Banjanin
Sonja
S
Matthews
Stephen G
SG
D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D005625:Frontal Lobe / Q000196:embryology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D005865:Gestational Age; D005938:Glucocorticoids / Q000378:metabolism* / Q000494:pharmacology; D006168:Guinea Pigs; D006179:Gyrus Cinguli / Q000196:embryology; D006624:Hippocampus / Q000196:embryology; D006854:Hydrocortisone / Q000097:blood; D008032:Limbic System / Q000196:embryology*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011985:Receptors, Serotonin / Q000235:genetics*; D013788:Thalamus / Q000196:embryology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D005938:Glucocorticoids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D011985:Receptors, Serotonin; D014157:Transcription Factors; C104425:serotonin 7 receptor; D003907:Dexamethasone; D006854:Hydrocortisone