Introduction: Exposure of developing female rats to estradiol during the perinatal period affects brain sexual differentiation and induces a long-lasting dysregulation of the gonadal axis with altered brain concentrations of progesterone and its neuroactive metabolite allopregnanolone. Aims: Allopregnanolone is a potent modulator of GABAA receptor expression and function; we thus evaluated whether the marked and persistent decrease in its concentrations, induced by neonatal estradiol treatment, alters GABAA receptor expression and function, stress sensitivity, and behavior in adult female rats. Methods: On the day of birth, pups received a single s.c. administration of beta-estradiol 3-benzoate (EB; 10 ug in 50 ul of sesame oil) or vehicle (controls). Experiments were performed in 60-120 days old rats. Results: Neonatal EB administration markedly decreased allopregnanolone levels in the cerebral cortex (-86%), hypothalamus (-55%) and hippocampus (-47%) of adult rats. This effect was associated with increased expression of extrasynaptic a4bd GABAA receptors and decreased expression of synaptic a1/a4bg2 GABAA receptors in the hippocampus. As a result, modulation of GABAergic tonic currents recorded in DG granule cells by THIP was increased in EB-treated rats vs. controls, with a larger holding current shift and a 26% enhancement of noise variance. EB treatment altered GABAergic phasic currents with a decrease in decay time and an increase (+76%) in frequency. Neonatal EB treatment increased dominant behaviors (duration: +142%, frequency: +121%) in the resident-intruder test, while locomotor activity, anxiety- and mood-related behaviors, as well as seizures sensitivity were not affected. Moreover, neonatal EB treatment induced a greater enhancement in the neurosteroid response to stress (5-fold), as well as in the extracellular dopamine concentrations (4-fold) in the prefrontal cortex of adult EB-treated rats exposed to foot-shock stress; this latest effect was normalized by restoring allopregnanolone concentrations. Conclusions: These results suggest that neonatal estradiol exposure plays a major role in regulating brain allopregnanolone concentrations, expression and function of synaptic and extrasynaptic GABAA receptors, agonistic behavior and stress sensitivity during adulthood. Given that allopregnanolone has been involved in stress homeostasis, the persistent decrease in its concentrations, induced by estradiol, may account for the heightened stress response. Likewise, the increased expression of hippocampal a4bd GABAA receptors may represent a homeostatic response to counteract the persistent decrease in allopregnanolone levels induced by estradiol. Thus, neonatal estradiol treatment alters inhibitory synaptic circuits and behavior in adult rats, in addition to its effects on brain sexual differentiation. Supported by Banco di Sardegna Foundation (2012.0255).
Neurosteroids during development: implications for GABAA receptor function and stress sensitivity in adulthood
Porcu P;Talani G;
2015
Abstract
Introduction: Exposure of developing female rats to estradiol during the perinatal period affects brain sexual differentiation and induces a long-lasting dysregulation of the gonadal axis with altered brain concentrations of progesterone and its neuroactive metabolite allopregnanolone. Aims: Allopregnanolone is a potent modulator of GABAA receptor expression and function; we thus evaluated whether the marked and persistent decrease in its concentrations, induced by neonatal estradiol treatment, alters GABAA receptor expression and function, stress sensitivity, and behavior in adult female rats. Methods: On the day of birth, pups received a single s.c. administration of beta-estradiol 3-benzoate (EB; 10 ug in 50 ul of sesame oil) or vehicle (controls). Experiments were performed in 60-120 days old rats. Results: Neonatal EB administration markedly decreased allopregnanolone levels in the cerebral cortex (-86%), hypothalamus (-55%) and hippocampus (-47%) of adult rats. This effect was associated with increased expression of extrasynaptic a4bd GABAA receptors and decreased expression of synaptic a1/a4bg2 GABAA receptors in the hippocampus. As a result, modulation of GABAergic tonic currents recorded in DG granule cells by THIP was increased in EB-treated rats vs. controls, with a larger holding current shift and a 26% enhancement of noise variance. EB treatment altered GABAergic phasic currents with a decrease in decay time and an increase (+76%) in frequency. Neonatal EB treatment increased dominant behaviors (duration: +142%, frequency: +121%) in the resident-intruder test, while locomotor activity, anxiety- and mood-related behaviors, as well as seizures sensitivity were not affected. Moreover, neonatal EB treatment induced a greater enhancement in the neurosteroid response to stress (5-fold), as well as in the extracellular dopamine concentrations (4-fold) in the prefrontal cortex of adult EB-treated rats exposed to foot-shock stress; this latest effect was normalized by restoring allopregnanolone concentrations. Conclusions: These results suggest that neonatal estradiol exposure plays a major role in regulating brain allopregnanolone concentrations, expression and function of synaptic and extrasynaptic GABAA receptors, agonistic behavior and stress sensitivity during adulthood. Given that allopregnanolone has been involved in stress homeostasis, the persistent decrease in its concentrations, induced by estradiol, may account for the heightened stress response. Likewise, the increased expression of hippocampal a4bd GABAA receptors may represent a homeostatic response to counteract the persistent decrease in allopregnanolone levels induced by estradiol. Thus, neonatal estradiol treatment alters inhibitory synaptic circuits and behavior in adult rats, in addition to its effects on brain sexual differentiation. 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.
