Neurosteroids are essential for aiding proper fetal neurodevelopment. Pregnancy compromises such as
preterm birth, prenatal stress and
intrauterine growth restriction are associated with an increased risk of developing behavioural and
mood disorders, particularly during adolescence. These pathologies involve the premature loss or alteration of trophic
steroid hormones reaching the fetus leading to impaired neurodevelopment. While the specific programming mechanisms are yet to be fully elucidated, in adult life, dysfunctions of
allopregnanolone action are prevalent in individuals with depression,
post-traumatic stress disorder and
anxiety disorders. The objective of this study was to assess if changes in concentrations of the
neurosteroid,
allopregnanolone, may be a fetal programming factor in priming the brain towards a negative behavioural phenotype during the childhood to adolescent period using a guinea pig model. Pregnant guinea pigs received either vehicle (45% (2-hydroxypropyl)-β-
cyclodextrin) or the 5α-reductase inhibitor,
finasteride (25mg/kg maternal weight) from gestational age 60 until spontaneous delivery (∼71days gestation). Male and female offspring from vehicle and
finasteride treated dams were tested at postnatal day 20 (juvenile-equivalence) in an open field arena, and hippocampus and amygdala subsequently assessed for neurological changes in markers of development and
GABA production pathways 24h later. Females with reduced
allopregnanolone exposure in utero displayed increased neophobic-like responses to a change in their environment compared to female controls. There were no differences in the neurodevelopmental markers assessed; MAP2, NeuN, MBP, GFAP or GAD67 between intrauterine
finasteride or vehicle exposure, in either the hippocampus or amygdala whereas GAT1 staining was decreased. This study indicates that an intrauterine reduction in the supply of
allopregnanolone programs vulnerability of female offspring to anxiety-like disorders in juvenility without impacting long term
allopregnanolone concentrations.