Decreased allopregnanolone induced by neonatal estradiol increases alpha4-beta-delta GABAA receptors, stress sensitivity and spatial learning in adult female rats

We have previously shown that exposure of developing female rats to estradiol during the perinatal period induced a long-lasting dysregulation of the gonadal axis and decreased brain allopregnanolone concentrations. We now examined whether these changes were associated with altered sensitivity to stress, learning and memory and expression of hippocampal extrasynaptic GABAA receptors (alpha4-beta-delta and alpha5-beta-gamma2) that are involved in anxiety and memory consolidation. A single administration of beta-estradiol 3-benzoate (EB) on the day of birth decreased allopregnanolone concentration in the hippocampus of adult female rats. Neonatal EB administration also increased the expression of alpha4 and delta subunits of the GABAA receptor in the extrasynaptic membrane fraction of hippocampus from adult female rats; alpha5 and gamma2 subunit expression was not altered in the same membrane fraction. Neonatal EB treatment decreased the latency and the cumulative search error to reach the platform in the Morris water maze suggesting improved learning in adult female rats. Neonatal EB treatment also enhanced memory performance during the probe trial. Finally, neonatal EB treatment induced a greater enhancement (4 fold) in the extracellular concentrations of dopamine in the prefrontal cortex of adult EB-treated rats exposed to foot-shock stress, an effect that was normalized by restoring allopregnanolone concentrations with progesterone administration. These results suggest that neonatal exposure to estradiol plays a major role in the regulation of hippocampal allopregnanolone concentrations, expression of extrasynaptic GABAA receptors, stress sensitivity and cognition during adulthood. The increased expression of alpha4-beta-delta GABAA receptors in the hippocampus may represent a homeostatic response to counteract the persistent decrease in allopregnanolone levels induced by neonatal treatment. Given that allopregnanolone has been reported to compensate response to stress and impair learning and memory, the persistent decrease in its concentrations may account for the improved cognition and higher sensitivity to stress observed in neonatal EB-treated rats. Acknowledgement: Supported by Banco di Sardegna Foundation (2012.0255).