Prenatal alcohol exposure alters GABA(A)alpha5 expression: a mechanism of alcohol-induced learning dysfunction

In a model for fetal alcohol syndrome (FAS), we have previously found an alteration in NMDA receptors suggesting mediation, at least in part, of alcohol-related learning deficit. NMDA and GABA receptors interact in a multisynaptic circuit for the regulation of the inhibitory tone through the CNS. The GABA receptor subunit GABA(A)alpha5 is involved in learning and is developmentally regulated, as it is excitatory in the perinatal brain and inhibitory in the adult. We were interested to evaluate alcohol's effect on GABA(A)alpha5 expression to further understand alcohol-induced learning dysfunction.

Timed, pregnant C57B16/J mice were treated on gestational day 8 with alcohol (25% alcohol, 0.03 mL/kg i.p.) or control (saline). Embryos and brains were harvested 10 days after treatment, and brains from adult offspring were collected after evaluation in the Morris Water Maze, a well-established test for spatial learning. Gene expression included samples from at least 3 litters per timepoint, and calibrator-normalized relative real-time polymerase chain reaction (PCR) was performed to quantify GABA(A)alpha5 with GAPDH standardization. Statistical analysis included analysis of variance (ANOVA).

Prenatal alcohol exposure significantly decreased GABA(A)alpha5 expression in the embryo (P < .02) and fetal brains (P < .01) 10 days after therapy. However, in adult brains GABA(A)alpha5 expression was increased versus controls (P < .01). As previously demonstrated, prenatal alcohol exposure resulted in deficits in adults learning the Morris Water Maze with controls learning faster (P < .05).

Prenatal alcohol exposure alters developmental GABA(A)alpha5 expression. This may further explain the long-lasting damage of alcohol on learning skills. Both the alcohol-induced reduction in the GABA(A)alpha5 subunit during development and up-regulation in adult brain may be related to learning deficits resulting in decreased learning potential caused by the developmental defect and an increased inhibition of learning resulting from increased expression as an adult. In combination with our previous findings, these suggest that alcohol-induced learning impairment is likely the result of alterations of both NMDA and GABA expression and function.