Fetal alcohol exposure alters neurosteroid modulation of hippocampal N-methyl-D-aspartate receptors

The actions of ethanol on brain ligand-gated ion channels have important ro les in the pathophysiology of alcohol-related neurodevelopmental disorders and fetal alcohol syndrome. Studies have shown that N-methyl-D-aspartate (N MDA) receptors are among the ligand-gated ion channels affected by prenatal ethanol exposure, We exposed pregnant dams to an ethanol-containing liquid diet that results in blood ethanol levels near the legal intoxication limi t in most states (0.08%). Primary cultures of hippocampal neurons were prep ared from the neonatal offspring of these dams, and NMDA receptor function was assessed by patch clamp electrophysiological techniques after 6-7 days in culture in ethanol-free media. Unexpectedly, we did not detect any chang es in hippocampal NMDA receptor function at either the whole-cell or single -channel levels. However, we determined that fetal alcohol exposure alters the actions of the neurosteroids pregnenolone sulfate and pregnenolone hemi succinate, which potentiate NMDA receptor function. Western immunoblot anal yses demonstrated that this alteration is not due to a change in the expres sion levels of NMDA receptor subunits. Importantly, in utero ethanol exposu re did not affect the actions of neurosteroids that inhibit NMDA receptor f unction, Moreover, the actions of pregnenolone sulfate on type A gamma -ami nobutyric acid and non-NMDA receptor function were unaltered by ethanol exp osure in utero, which suggests that the alteration is specific to NMDA rece ptors. These findings are significant because they provide, at least in par t, a plausible mechanistic explanation for the alterations in the behaviora l responses to neurosteroids found in neonatal rats prenatally exposed to e thanol and to other forms of maternal stress (Zimmerberg, B,, and McDonald, B, C. (1996) Pharmacol. Biochem. Behav. 55, 541-547).