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 decreased progesterone secretion, and a persistent reduction in brain concentrations of its neuroactive metabolite allopregnanolone. Given that allopregnanolone is a potent modulator of GABAA receptor (GABAAR) expression and function, we evaluated whether neonatal estradiol treatment, alters GABAAR expression and function in the hippocampus of adult female rats. On the day of birth, pups received a single administration of b-estradiol 3-benzoate (EB; 10 microg in 50 microl of sesame oil, s.c.) or vehicle. Experiments were performed in 90-120 days old rats. Given that GABAAR subunit expression varies in response to steroid fluctuations that occur during the estrus cycle, vehicle-treated rats in the proestrus and diestrus 1 phases were used as controls. Neonatal EB treatment increased the abundance of extrasynaptic alpha4 (+47%) and delta (+30%) subunits (p<0.05), and decreased the abundance of synaptic alpha1 (-36%), alpha4 (-32%), and gamma2 (-36%) subunits (p<0.05), compared to vehicle-treated rats in proestrus. Plasma allopregnanolone levels in the same rats were higher in diestrus 1 vehicle-treated rats vs. proestrus ones (+30%, p<0.05), and were decreased by neonatal EB treatment compared to vehicle-treated rats in proestrus (-69%, p<0.001) and diestrus 1 (-76%, p<0.001). Modulation of GABAergic tonic currents recorded in DG granule cells was increased in EB-treated rats and vehicle-treated rats in diestrus 1, compared to vehicle-treated rats in proestrus, with a THIP-induced larger shift in holding current and greater increase in the noise variance (p<0.05). EB treatment also altered GABAergic phasic currents with a decrease in decay time (p<0.05). The changes in the expression and function of GABAARs, induced by neonatal EB treatment, may not be related to the fluctuations in allopregnanolone concentrations, given that vehicle-treated rats in diestrus, which have opposite neurosteroid levels than EB-treated rats, show the same functional changes in GABAARs as EB-treated rats. Rather, these changes may represent a compensatory mechanism to counteract the persistent long-term reduction in allopregnanolone concentrations, induced by neonatal estradiol treatment. These enduring changes in GABAAR plasticity may be relevant for regulation of neuronal excitability in the hippocampus and for the etiology of psychiatric disorders that originate in development and show sex differences.
Neonatal estradiol exposure to female rats changes GABAA receptor expression and function during adulthood
Porcu P;Talani G;Sanna E;Concas A
2016
Abstract
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 decreased progesterone secretion, and a persistent reduction in brain concentrations of its neuroactive metabolite allopregnanolone. Given that allopregnanolone is a potent modulator of GABAA receptor (GABAAR) expression and function, we evaluated whether neonatal estradiol treatment, alters GABAAR expression and function in the hippocampus of adult female rats. On the day of birth, pups received a single administration of b-estradiol 3-benzoate (EB; 10 microg in 50 microl of sesame oil, s.c.) or vehicle. Experiments were performed in 90-120 days old rats. Given that GABAAR subunit expression varies in response to steroid fluctuations that occur during the estrus cycle, vehicle-treated rats in the proestrus and diestrus 1 phases were used as controls. Neonatal EB treatment increased the abundance of extrasynaptic alpha4 (+47%) and delta (+30%) subunits (p<0.05), and decreased the abundance of synaptic alpha1 (-36%), alpha4 (-32%), and gamma2 (-36%) subunits (p<0.05), compared to vehicle-treated rats in proestrus. Plasma allopregnanolone levels in the same rats were higher in diestrus 1 vehicle-treated rats vs. proestrus ones (+30%, p<0.05), and were decreased by neonatal EB treatment compared to vehicle-treated rats in proestrus (-69%, p<0.001) and diestrus 1 (-76%, p<0.001). Modulation of GABAergic tonic currents recorded in DG granule cells was increased in EB-treated rats and vehicle-treated rats in diestrus 1, compared to vehicle-treated rats in proestrus, with a THIP-induced larger shift in holding current and greater increase in the noise variance (p<0.05). EB treatment also altered GABAergic phasic currents with a decrease in decay time (p<0.05). The changes in the expression and function of GABAARs, induced by neonatal EB treatment, may not be related to the fluctuations in allopregnanolone concentrations, given that vehicle-treated rats in diestrus, which have opposite neurosteroid levels than EB-treated rats, show the same functional changes in GABAARs as EB-treated rats. Rather, these changes may represent a compensatory mechanism to counteract the persistent long-term reduction in allopregnanolone concentrations, induced by neonatal estradiol treatment. These enduring changes in GABAAR plasticity may be relevant for regulation of neuronal excitability in the hippocampus and for the etiology of psychiatric disorders that originate in development and show sex differences.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
