Allopregnanolone, a neuroactive metabolite of progesterone acting at extrasynaptic GABAA receptors, has been reported to impair spatial learning and memory in rodents. 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 the brain concentrations of allopregnanolone [1, 2]. We now examined whether these changes were associated with altered learning and memory and expression of hippocampal extrasynaptic GABAA receptors (alpha4-beta-delta and alpha5-beta-gamma2) that seem to be essential for consolidation of memory [3]. A single administration of beta-estradiol 3-benzoate (EB; 10 micrograms, s.c.) on the day of birth induced a marked and persistent decrease in the concentrations of allopregnanolone and progesterone in the hippocampus (-46% and -75%, respectively) of adult female rats. In contrast, the same treatment did not alter the hippocampal concentrations of THDOC, DHEA, or 17beta-estradiol in adult female rats. Neonatal administration of EB also increased the expression of the alpha4 and delta subunits of the GABAA receptor (+40% and +25%, respectively) in the extrasynaptic membrane fraction of hippocampus from adult female rats, while the alpha5 and gamma2 subunits expression was not altered in the same membrane fraction. Neonatal EB treatment altered performance in the Morris water maze test in adult female rats. Specifically, neonatal administration of EB decreased the latency to reach the hidden platform during training, and increased the swim speed and the total proximity to the platform, suggesting improved spatial learning. Furthermore, neonatal treatment with EB decreased the average proximity to the platform and increased both the time spent and the number of entries in the east quadrant during the probe trial, suggesting enhanced memory performance. Overall, these results suggest that neonatal exposure to estradiol plays a major role in the regulation of both hippocampal allopregnanolone concentrations and the expression of extrasynaptic GABAA receptors 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 estradiol treatment. However, given that alpha4-beta-delta GABAA receptors have been associated to an impairment of learning and memory, the persistent decrease in allopregnanolone may account for the improvement in spatial learning and memory through other mechanisms. This work was supported by Banco di Sardegna Foundation (2012.0255).
Neonatal estradiol treatment decreases hippocampal allopregnanolone concentrations, up-regulates extrasynaptic GABAA receptors and increases spatial learning and memory in adult female rats
Porcu P;Concas A
2015
Abstract
Allopregnanolone, a neuroactive metabolite of progesterone acting at extrasynaptic GABAA receptors, has been reported to impair spatial learning and memory in rodents. 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 the brain concentrations of allopregnanolone [1, 2]. We now examined whether these changes were associated with altered learning and memory and expression of hippocampal extrasynaptic GABAA receptors (alpha4-beta-delta and alpha5-beta-gamma2) that seem to be essential for consolidation of memory [3]. A single administration of beta-estradiol 3-benzoate (EB; 10 micrograms, s.c.) on the day of birth induced a marked and persistent decrease in the concentrations of allopregnanolone and progesterone in the hippocampus (-46% and -75%, respectively) of adult female rats. In contrast, the same treatment did not alter the hippocampal concentrations of THDOC, DHEA, or 17beta-estradiol in adult female rats. Neonatal administration of EB also increased the expression of the alpha4 and delta subunits of the GABAA receptor (+40% and +25%, respectively) in the extrasynaptic membrane fraction of hippocampus from adult female rats, while the alpha5 and gamma2 subunits expression was not altered in the same membrane fraction. Neonatal EB treatment altered performance in the Morris water maze test in adult female rats. Specifically, neonatal administration of EB decreased the latency to reach the hidden platform during training, and increased the swim speed and the total proximity to the platform, suggesting improved spatial learning. Furthermore, neonatal treatment with EB decreased the average proximity to the platform and increased both the time spent and the number of entries in the east quadrant during the probe trial, suggesting enhanced memory performance. Overall, these results suggest that neonatal exposure to estradiol plays a major role in the regulation of both hippocampal allopregnanolone concentrations and the expression of extrasynaptic GABAA receptors 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 estradiol treatment. However, given that alpha4-beta-delta GABAA receptors have been associated to an impairment of learning and memory, the persistent decrease in allopregnanolone may account for the improvement in spatial learning and memory through other mechanisms. This work was supported by Banco di Sardegna Foundation (2012.0255).I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
