|Abstract: ||Exposure of female rats to estradiol during the perinatal period affects brain sexual differentiation and induces a long-lasting dysregulation of the gonadal axis with reduced progesterone secretion, associated with persistent reductions in the cerebrocortical, hypothalamic and plasma concentrations of its metabolite, allopregnanolone. Given that allopregnanolone is a potent positive modulator of GABAA receptor (GABAAR) expression and function, it has been evaluated whether neonatal estradiol treatment affects, during adulthood, GABAAR expression and function in the hippocampus, an area that exhibits the two components, tonic and phasic, of the inhibitory GABAergic transmission. Neonatal estradiol administration to female rats induced a selective reduction in hippocampal allopregnanolone levels in adult animals, associated with increased expression of extrasynaptic α4/δ subunit-containing GABAARs and tonic currents. Moreover, the same treatment altered the expression of synaptic receptors containing α1/α4/γ2 subunits as well as phasic currents. The changes in the expression and function of GABAARs, induced by neonatal estradiol treatment, may not be related to the fluctuations in allopregnanolone concentrations, given that vehicle-treated rats in diestrus 1, which have opposite neurosteroid levels than estradiol-treated rats, show the same functional changes in GABAARs as estradiol-treated rats.
Allopregnanolone plays an important role in hypothalamic-pituitary-adrenal (HPA) homeostasis and in the stress response. Thus, it has been examined whether neonatal exposure to estradiol was associated with altered HPA axis responsiveness and sensitivity to stress in the adulthood. Neonatal estradiol treatment induced a marked increase in brain and plasma allopregnanolone levels following foot-shock stress, an effect not observed in control animals. Moreover, acute stress increased brain and plasma corticosterone levels to a similar extent in vehicle- and estradiol-treated rats, suggesting that the greater sensitivity of estradiol-treated rats to stress might not involve a dysregulation of the HPA axis. Indeed, the dexamethasone suppression test revealed that hypothalamic and plasma corticosterone levels were decreased to a similar extent in both estradiol- and vehicle-treated adult female rats; moreover, expression of hippocampal glucocorticoid and mineralocorticoid receptors, as well as hypothalamic glucocorticoid receptors, did not differ between estradiol- and vehicle-treated adult female rats, suggesting that the increased stress sensitivity in estradiol-treated rats is independent of HPA axis function. Finally, neonatal estradiol treatment induced a greater enhancement in the extracellular concentrations of dopamine in the prefrontal cortex of adult 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 and function of GABAARs, as well as stress sensitivity during adulthood. The increased expression and function of α4/δ GABAARs 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, the persistent decrease in its concentrations may account for the higher sensitivity to stress observed in neonatal estradiol-treated rats. These enduring changes in GABAAR plasticity and stress sensitivity may be relevant for regulation of neuronal excitability and for the etiology of psychiatric disorders that originate in development and show sex differences in their prevalence.|