title: Steroid-sensitive GABAA receptors in the fetal sheep brain.
abstract: Neuroactive steroids such as allopregnanolone (3 alpha-hydroxy-5 alpha-pregnan-20-one) influence central nervous system (CNS) excitability by increasing GABA (gamma aminobutyric acid) inhibitory activity. Allopregnanolone concentrations are higher in the fetal compared to the adult ovine brain, suggesting that this neurosteroid may have a role in regulating fetal CNS activity during gestation. We examined the localisation of allopregnanolone-sensitive GABA(A) receptors in the fetal brain to determine if their sensitivity to allopregnanolone changed during late gestation. The binding of [(35)S] tert-butylbicyclophosothionate (TBPS) was used to identify the GABA-chloride ion receptor complex in fetal sheep brains at 90-95, 115-120 and 140-145 days gestational age (GA; term approximately 147 days), by autoradiography. Allopregnanolone (200 nM) reduced [(35)S]TBPS binding by 70-100% throughout the brain at all fetal ages examined. The levels of [(35)S]TBPS binding increased with advancing gestation in all regions examined except some areas of the medulla. Functionally related nuclei and brain areas associated with regulating somato/viscerosensory functions displayed high levels of [(35)S]TBPS binding from mid-gestation. These results indicate that allopregnanolone may interact with GABA(A) receptors to inhibit fetal CNS activity from mid-gestation. This inhibition may contribute to maintaining the sleep-like behaviour and low incidence of arousal-type activity typical of fetal life, and may be neuroprotective by limiting excitatory neurotransmission.
authors.affiliation: Department of Physiology, Monash University, P.O. Box, Building 13F, Clayton, Victoria 3800, Australia.
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Crossley
authors.forename: Ilias
authors.initials: I
authors.lastname: Nitsos
authors.forename: David W
authors.initials: DW
authors.lastname: Walker
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lawrence
authors.forename: Philip M
authors.initials: PM
authors.lastname: Beart
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Hirst
mesh_terms: D000367:Age Factors; D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000737:chemistry / Q000378:metabolism*; D005865:Gestational Age; D011247:Pregnancy; D011280:Pregnanolone / Q000032:analysis / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011963:Receptors, GABA-A / Q000032:analysis / Q000378:metabolism*; D012756:Sheep / Q000196:embryology / Q000378:metabolism*
chemical_list: D011963:Receptors, GABA-A; D011280:Pregnanolone