Physiological modulation of GABAA receptor plasticity by progesterone metabolites (original) (raw)
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Proceedings of the National Academy of Sciences, 1998
The relation between changes in brain and plasma concentrations of neurosteroids and the function and structure of ␥-aminobutyric acid type A (GABA A ) receptors in the brain during pregnancy and after delivery was investigated in rats. In contrast with plasma, where all steroids increased in parallel, the kinetics of changes in the cerebrocortical concentrations of progesterone, allopregnanolone (AP), and allotetrahydrodeoxycorticosterone (THDOC) diverged during pregnancy. Progesterone was already maximally increased between days 10 and 15, whereas AP and allotetrahydrodeoxycorticosterone peaked around day 19. The stimulatory effect of muscimol on 36 Cl ؊ uptake by cerebrocortical membrane vesicles was decreased on days 15 and 19 of pregnancy and increased 2 days after delivery. Moreover, the expression in cerebral cortex and hippocampus of the mRNA encoding for ␥2L GABA A receptor subunit decreased during pregnancy and had returned to control values 2 days after delivery. Also ␣1,␣2, ␣3, ␣4, 1, 2, 3, and ␥2S mRNAs were measured and failed to change during pregnancy. Subchronic administration of finasteride, a 5␣-reductase inhibitor, to pregnant rats reduced the concentrations of AP more in brain than in plasma as well as prevented the decreases in both the stimulatory effect of muscimol on 36 Cl ؊ uptake and the decrease of ␥2L mRNA observed during pregnancy. These results indicate that the plasticity of GABA A receptors during pregnancy and after delivery is functionally related to f luctuations in endogenous brain concentrations of AP whose rate of synthesis͞metabolism appears to differ in the brain, compared with plasma, in pregnant rats.
Proceedings of the National Academy of Sciences of the United States of America, 1998
The relation between changes in brain and plasma concentrations of neurosteroids and the function and structure of gamma-aminobutyric acid type A (GABAA) receptors in the brain during pregnancy and after delivery was investigated in rats. In contrast with plasma, where all steroids increased in parallel, the kinetics of changes in the cerebrocortical concentrations of progesterone, allopregnanolone (AP), and allotetrahydrodeoxycorticosterone (THDOC) diverged during pregnancy. Progesterone was already maximally increased between days 10 and 15, whereas AP and allotetrahydrodeoxycorticosterone peaked around day 19. The stimulatory effect of muscimol on 36Cl- uptake by cerebrocortical membrane vesicles was decreased on days 15 and 19 of pregnancy and increased 2 days after delivery. Moreover, the expression in cerebral cortex and hippocampus of the mRNA encoding for gamma2L GABAA receptor subunit decreased during pregnancy and had returned to control values 2 days after delivery. Also alpha1,alpha2, alpha3, alpha4, beta1, beta2, beta3, and gamma2S mRNAs were measured and failed to change during pregnancy. Subchronic administration of finasteride, a 5alpha-reductase inhibitor, to pregnant rats reduced the concentrations of AP more in brain than in plasma as well as prevented the decreases in both the stimulatory effect of muscimol on 36Cl- uptake and the decrease of gamma2L mRNA observed during pregnancy. These results indicate that the plasticity of GABAA receptors during pregnancy and after delivery is functionally related to fluctuations in endogenous brain concentrations of AP whose rate of synthesis/metabolism appears to differ in the brain, compared with plasma, in pregnant rats.
Neurosteroid modulation of GABAA receptors
Progress in Neurobiology, 2003
Certain metabolites of progesterone and deoxycorticosterone are established as potent and selective positive allosteric modulators of the ␥-aminobutyric acid type A (GABA A ) receptor. Upon administration these steroids exhibit clear behavioural effects that include anxiolysis, sedation and analgesia, they are anticonvulsant and at high doses induce a state of general anaesthesia, a profile consistent with an action to enhance neuronal inhibition. Physiologically, peripherally synthesised pregnane steroids derived from endocrine glands such as the adrenals and ovaries function as hormones by crossing the blood brain barrier to influence neuronal signalling. However, the demonstration that certain neurons and glial cells within the central nervous system (CNS) can synthesize these steroids either de novo, or from peripherally derived progesterone, has led to the proposal that these steroids (neurosteroids) can additionally function in a paracrine manner, to locally influence GABAergic transmission. Steroid levels are known to change dynamically, for example in stress and during pregnancy. Given that GABA A receptors are ubiquitously expressed throughout the central nervous system, such changes in steroid levels would be predicted to cause a global enhancement of inhibitory neurotransmission throughout the brain, a scenario that would seem incompatible with a physiological role as a selective neuromodulator. Here, we will review emerging evidence that the GABA-modulatory actions of the pregnane steroids are highly selective, with their actions being brain region and indeed neuron dependent. Furthermore, the sensitivity of GABA A receptors is not static but can dynamically change. The molecular mechanisms underpinning this neuronal specificity will be discussed with particular emphasis being given to the role of GABA A receptor isoforms, protein phosphorylation and local steroid metabolism and synthesis.
Pharmacol Biochem Behav, 2006
Expression of specific gamma-aminobutyric acid type A (GABA(A)) receptor subunit genes in neurons is affected by endogenous modulators of receptor function such as neuroactive steroids. Neuroactive steroids such as the progesterone metabolite allopregnanolone might thus exert differential effects on GABA(A) receptor plasticity in neurons, likely accounting for some of the physiological actions of these compounds. Here we summarise experimental data obtained in vitro that show how fluctuations in the concentration of progesterone regulate both the expression and function of GABA(A) receptors. The data described in this manuscript are in agreement with the notion that fluctuations in the concentrations of progesterone and its metabolite allopregnanolone play a major role in the temporal pattern of expression of various subunits of the GABA(A) receptor. Thus, rapid and long-lasting increases or decreases in the concentrations of these steroid derivatives observed in physiological and patho-physiological conditions, or induced by pharmacological treatments, might elicit selective changes in GABA(A) receptor gene expression and function in specific neuronal populations. Given both the importance of GABA(A) receptors in the regulation of neuronal excitability and the large fluctuations in the plasma and brain concentrations of neuroactive steroids associated with physiological conditions and the response to environmental stimuli, these compounds are likely among the most relevant endogenous modulators that could affect emotional and affective behaviors.
Journal of Neuroendocrinology, 2007
The 3α-hydroxy,5α-reduced pregnane steroids, allopregnanolone and allotetrahydrodeoxycorticosterone, are the most potent endogenous positive modulators of GABAA receptor-mediated inhibition. This study presents the first immunohistochemical examination of the cellular distribution of 3α-hydroxy,5α-reduced pregnane steroids across the brain. We found a widespread distribution in the adult rat, with dense immunolabelling in the olfactory bulb, striatum and cerebral cortex, and lower density labelling in the brainstem reticular formation. In general terms, this distribution accords with the regional concentrations of 3α-hydroxy,5α-reduced steroids determined, in other laboratories, by brain region sampling and either gas chromatography-mass fragmentography or radioimmunoassay. However, immunohistochemistry allowed for a more detailed examination of regional distribution and cellular specificity. All immunoreactivity was confined to the cell bodies and thick dendrites of neurones; no identifiable glia were labelled. In most brain areas, the location and morphology of labelled cells identified them as excitatory neurones. In addition, cell populations known to be projecting GABAergic neurones (e.g. cerebellar Purkinje cells) were immunoreactive, whereas local inhibitory neurones generally were not. The cellular distribution of 3α-hydroxy,5α-reduced steroids suggests that sensory, motor, limbic and homeostatic systems can be influenced by neurosteroids at multiple stages of processing.
Neurosteroid regulation of GABAA receptors: Focus on the α4 and δ subunits
Pharmacology & Therapeutics, 2007
Neurosteroids, such as the progesterone metabolite 3α-OH-5α[β]-pregnan-20-one (THP or [allo] pregnanolone), function as potent positive modulators of the GABA A receptor (GABAR) when acutely administered. However, fluctuations in the circulating levels of this steroid at puberty, across endogenous ovarian cycles, during pregnancy or following chronic stress produce periods of prolonged exposure and withdrawal, where changes in GABAR subunit composition may occur as compensatory responses to sustained levels of inhibition. A number of laboratories have demonstrated that both chronic administration of THP as well as its withdrawal transiently increase expression of the α4 subunit of the GABAR in several areas of the central nervous system (CNS) as well as in in vitro neuronal systems. Receptors containing this subunit are insensitive to benzodiazepine (BDZ) modulation and display faster deactivation kinetics, which studies suggest underlie hyperexcitability states. Similar increases in α4 expression are triggered by withdrawal from other GABA-modulatory compounds, such as ethanol and BDZ, suggesting a common mechanism. Other studies have reported puberty or estrous cycle-associated increases in δ-GABAR, the most sensitive target of these steroids which underlies a tonic inhibitory current. In the studies reported here, the effect of steroids on inhibition, which influence anxiety state and seizure susceptibility, depend not only on the subunit composition of the receptor but also on the direction of Clcurrent generated by these target receptors. The effect of neurosteroids on GABAR function thus results in behavioral outcomes relevant for pubertal mood swings, premenstrual dysphoric disorder and catamenial epilepsy, which are due to fluctuations in endogenous steroids.
Neurosteroid modulation of GABAA receptors in the developing rat brain cortex
Neurochemistry International, 1997
The allosteric modulation of GABA A receptors in the rat brain cortex by neurosteroids was studied at di}erent developmental stages[ GABA A receptors were identi_ed using ð 2 HŁmuscimol binding to membrane preparations obtained from embryos and neonates "postnatal day 9*PN9^postnatal day 4* PN4#[ Data analysis disclosed a unique population of binding sites at all ages tested[ An increase in the number of receptors was observed during development reaching almost adult levels at PN4[ The neu! rosteroids pregnanolone and allopregnanolone failed to modulate ð 2 HŁmuscimol speci_c binding in embryos and neonates\ but a positive modulation was obtained in 4!day old animals[ The addition of 0 mM pregnanolone induced a 2Ð5!fold increase ð 2 HŁmuscimol a.nity in PN4 "n 2^P ³ 9[92#\ and a 1!fold increase in receptors number in adults "n 2^P ³ 9[92#[ The di}erences observed in allosteric modulation during development suggest that a change occurred during the _rst week of life\ and this change might a}ect GABA A receptor function[ Þ 0886 Elsevier Science Ltd
Journal of Neuroscience, 2009
Pregnancy is associated with changes in mood and anxiety level as well as with marked hormonal fluctuations. Increases in the brain concentrations of neuroactive steroids during pregnancy in rats are accompanied by changes in expression of subunits of the GABA type A receptor (GABA A -R) in the brain. Granule cells of the dentate gyrus (DGGCs) exhibit two components of inhibitory GABAergic transmission: a phasic component mediated by synaptic GABA A -Rs, and a tonic component mediated by extrasynaptic GABA A -Rs. Recordings of GABAergic currents were obtained from hippocampal slices prepared from rats in estrus, at pregnancy day 15 (P15) or P19, or at 2 d after delivery. Exogenous GABA or 3␣,5␣-THP induced an increase in tonic current in DGGCs that was significantly greater at P19 than in estrus. Neither tonic nor phasic currents were affected by pregnancy in CA1 pyramidal cells. Immunohistochemical analysis revealed a marked increase in the abundance of the ␦ subunit of the GABA A -R and a concomitant decrease in that of the ␥ 2 subunit in the hippocampus at P19. Expression of the ␣ 4 subunit did not change during pregnancy but was increased 2 d after delivery. Treatment of rats from P12 to P18 with the 5␣-reductase inhibitor finasteride prevented the changes in tonic current and in ␦ and ␥ 2 subunit expression normally apparent at P19. These data suggest that the number of extrasynaptic GABA A -Rs is increased in DGGCs during late pregnancy as a consequence of the associated marked fluctuations in the brain levels of neuroactive steroids.
Journal of Neurochemistry, 2006
Type A receptors for GABA (GABA A receptors) that contain the d subunit are located predominantly at extrasynaptic sites and are implicated in modulation of neuronal excitability through tonic inhibition. We have examined the effects of chronic exposure to and subsequent withdrawal of progesterone or the progesterone metabolite 3a-hydroxy-5a-pregnan-20-one (3a,5a-THPROG) on expression of the d subunit of GABA A receptors and on receptor function in cultured rat hippocampal neurons. Progesterone treatment for 1 day increased the amounts of both d subunit mRNA and protein, whereas such treatment for 6 days induced marked decreases in the abundance of both the mRNA and protein. Subsequent progesterone withdrawal up-regulated expression of the d subunit, which was significantly increased at 9-12 h after withdrawal. These effects of progesterone were mimicked by 3a,5a-THPROG and blocked by the 5a-reductase inhibitor finasteride. They were also accompanied by parallel changes in the function of GABA A receptors in hippocampal neurons. These results show that chronic exposure to and withdrawal of progesterone induce differential effects on both expression of the d subunit of GABA A receptors and receptor function that are mediated by 3a,5a-THPROG. They are consistent with the notion that this progesterone metabolite plays a key physiological role in modulation of GABAergic synapses.