Synthetic glucocorticoids (sGCs) are routinely used to treat women at risk of preterm labour to promote fetal lung maturation. There is now strong evidence that exposure to excess glucocorticoid during periods of rapid brain development has permanent consequences on endocrine function and behaviour in the offspring. Prenatal sGC exposure alters the expression of N-methyl D-aspartate receptor (NMDA-R) subunits in the fetal and neonatal hippocampus. Given the integral role of the NMDA-R in synaptic plasticity, we hypothesized that prenatal sGC exposure will have effects on hippocampal long-term potentiation (LTP) after birth. Further, this may occur in either the presence or absence of elevated cortisol concentrations, in vitro. Pregnant guinea pigs were injected with betamethasone (Beta, 1mg/kg) or vehicle on gestational days (gd) 40, 41, 50, 51, 60 and 61 (term~70 days), a regimen comparable to that given to pregnant women. On post-natal day 21, LTP was examined at Schaffer-collateral synapses in the CA1 region of hippocampal slices prepared from juvenile animals exposed to betamethasone or vehicle, in utero. Subsequently, the acute glucocorticoid (GR)- and mineralocorticoid receptor (MR)-dependent effects of cortisol (0.1-10 µM; bath applied 30 min before LTP induction) were examined. There was no effect of prenatal sGC treatment on LTP under basal conditions. The application of 10 µM cortisol depressed excitatory synaptic transmission in all treatment groups regardless of sex. Similarly, LTP was depressed by 10 µM cortisol in all groups, with the exception of Beta-exposed females, where LTP was unaltered. Hippocampal MR and GR protein levels were increased in Beta females, but not in any other prenatal treatment group. This study reveals sex-specific effects of prenatal sGC exposure on LTP in the presence of elevated cortisol, a situation that would occur in vivo during stress.