title: Cerebellar Changes in Guinea Pig Offspring Following Suppression of Neurosteroid Synthesis During Late Gestation.
abstract: Elevated gestational concentrations of allopregnanolone are essential for the development and neuroprotection of the foetal brain. Preterm birth deprives the foetus of these high levels of allopregnanolone, which may contribute to the associated adverse effects on cerebellar development. Preterm birth alters expression of GABAAreceptor subunit composition, which may further limit neurosteroid action. The objective of this study was to determine the effects of suppression of allopregnanolone levels on the markers of development and functional outcome. Pregnant guinea pigs were treated with finasteride at a dose (25 mg/kg maternal weight) shown to suppress allopregnanolone between 60 days of gestation until delivery (term ∼71 days). The cerebella from neonates, whose mothers were treated with finasteride or vehicle during pregnancy, were collected at postnatal age 8. Pups that received finasteride displayed significantly greater glial fibrillary acid protein area coverage and reduced GABAAreceptor α6-subunit messenger RNA within the cerebellum than pups that were exposed to vehicle. These findings indicate that loss of neurosteroid action on the foetal brain in late gestation produces prolonged astrocyte activation and reductions in GABAAreceptor α6-subunit expression. These changes may contribute to the long-term changes in function associated with preterm birth.
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, 2308, New South Wales, Australia. Angela.Cumberland@uon.edu.au.|Hunter Medical Research Institute, Mothers and Babies Research Centre, Newcastle, 2305, New South Wales, Australia. Angela.Cumberland@uon.edu.au.
authors.forename: Angela L
authors.initials: AL
authors.lastname: Cumberland
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, 2308, New South Wales, Australia.|Hunter Medical Research Institute, Mothers and Babies Research Centre, Newcastle, 2305, New South Wales, Australia.
authors.forename: Hannah K
authors.initials: HK
authors.lastname: Palliser
authors.affiliation: Hudson Institute of Medical Research, Clayton, 3168, Victoria, Australia.
authors.forename: David W
authors.initials: DW
authors.lastname: Walker
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, 2308, New South Wales, Australia.|Hunter Medical Research Institute, Mothers and Babies Research Centre, Newcastle, 2305, New South Wales, Australia.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Hirst
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002531:Cerebellum / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D018120:Finasteride; D006168:Guinea Pigs; D007150:Immunohistochemistry; D008297:Male; D023421:Models, Animal; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011248:Pregnancy Complications; D011280:Pregnanolone / Q000097:blood / Q000172:deficiency*; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D011963:Receptors, GABA-A / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D011963:Receptors, GABA-A; D018120:Finasteride; D011280:Pregnanolone; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase
keywords: Allopregnanolone; Astrocyte; Cerebellum; Finasteride; GABAA receptor