Neurosteroids and Gabaergic Signaling in Health and Disease
Total Page：16
File Type：pdf, Size：1020Kb
DOI 10.1515/bmc-2012-0033 BioMol Concepts 2013; 4(1): 29–42 Review Georgina MacKenzie and Jamie Maguire * Neurosteroids and GABAergic signaling in health and disease Abstract: Endogenous neurosteroids such as allopregna- those derived from the local metabolism of peripherally nolone, allotetrahydrodeoxycorticosterone, and andros- derived steroid precursors such as, progesterone, corticos- tanediol are synthesized either de novo in the brain from terone, or testosterone (1 – 3) . Neurosteroids are modula- cholesterol or are generated from the local metabolism of tors of aminobutyric acid type A receptors (GABA A Rs) and peripherally derived progesterone or corticosterone. Fluctu- can induce analgesic, anxiolytic, sedative, anesthetic, and ations in neurosteroid concentrations are important in the anticonvulsant effects (4, 5) . The ability of neurosteroids regulation of a number of physiological responses includ- to modulate GABAA R function was first shown in 1984 by ing anxiety and stress, reproductive, and sexual behaviors. Harrison and Simmonds who demonstrated that alpha- These effects are mediated in part by the direct binding xalone, a synthetic neuroactive steroid with anesthetic γ of neurosteroids to -aminobutyric acid type-A receptors properties, potently potentiated GABAA R currents (6) . (GABAA Rs), resulting in the potentiation of GABAA R-medi- This result was repeated shortly afterward with the endo- δ α α ated currents. Extrasynaptic GABAA Rs containing the genous neurosteroids 5 -pregnane-3 -ol-20-one (allopre- subunit, which contribute to the tonic conductance, are gnanolone) and 5 α -pregnane-3 α ,21-diol-20-one (THDOC) particularly sensitive to low nanomolar concentrations of (7) . Fluctuations in the concentration of endogenous neurosteroids and are likely their preferential target. Con- neurosteroids and changes in GABAergic signaling have sidering the large charge transfer generated by these persis- been implicated in a variety of physiological and patho- tently open channels, even subtle changes in neurosteroid physiological conditions including stress, pregnancy, concentrations can have a major impact on neuronal excit- reproductive/sexual behaviors, depression, and epilepsy ability. Consequently, aberrant levels of neurosteroids have (8 – 15) . Here we review the neurosteroid-mediated regula- been implicated in numerous disorders, including, but not tion of GABAergic transmission, the effects on neuronal limited to, anxiety, neurodegenerative diseases, alcohol excitability, and the implications for health and disease. abuse, epilepsy, and depression. Here we review the modu- lation of GABA A R by neurosteroids and the consequences for health and disease. Neurosteroidogenesis Keywords: allopregnanolone; γ -aminobutyric acid There are three main classes of neurosteroids: the pregnane (GABA); neurosteroids; allotetrahydrodeoxycorticosterone (e.g., allopregnanolone), the sulfated (e.g., dehydroepian- (THDOC). drosterone sulfate, or DHEAS), and the androstane (e.g., androstanediol), which are classified according to their *Corresponding author: Jamie Maguire, Department of structural homology (9) (Figure 1 ). The 3-α hydroxy ring Neuroscience , School of Medicine, Tufts University, Boston, A-reduced pregnane steroids, such as allopregnanolone MA 02111 , USA , e-mail: [email protected] and THDOC, are the most potent positive modulators of Georgina MacKenzie: Department of Neuroscience , School of GABA Rs and will be the focus of this review whereas; Medicine, Tufts University, Boston, MA 02111 , USA A the sulfated neurosteroids are often inhibitory and act as noncompetitive antagonists at GABAA Rs (16) . Allopregna- nolone and THDOC can be synthesized from cholesterol Introduction by a series of steroidogenic enzymes [for reviews, see (2, 5, 17, 18) ] (Figure 1). Briefly, the key pathways are as follows: The term neurosteroids was first introduced in the 1980s cholesterol is transported into the inner mitochondrial by Baulieu to describe steroids produced de novo in the membrane via the steroidogenic acute regulatory protein brain from cholesterol; it was later expanded to include (StAR) and translocator protein 18 kDa (TSPO), also known 30 G. MacKenzie and J. Maguire: Neurosteroids and GABAergic signaling O P450SCC H - O H -O Cholesterol Pregnenolone 3β-HSD O O Progesterone 5α-reductase p450c21 O - H O O O - H O H O O 3,20-Allopregnanedione 11-deoxycorticosterone Testosterone 3α-HSD 5α-reductase 5α-reductase O - H O O O - H H -O H O H O H Allopregnanolone 5-alpha-dihydrodeoxycorticosterone Androstanolone (dihydrotestosterone) 3α-HSD 3α-HSD O - H O O - H H - O H H - O H Allotetrahydrodeoxycorticosterone Androstanediol (THDOC) Figure 1 The major biosynthetic pathways in the synthesis of allopregnanolone (3 α ,5 α -tetrahydroprogesterone, 5α -pregnan-3α -ol-20-one, 3 α -hydroxy-5α -pregnan-20-one, or 5 α 3 α -THPROG), THDOC (allotetrahydrodeoxycorticosterone, 5α -pregnane-3 α ,21-diol-20-one, or 5 α 3 α -THDOC), and androstanediol (5α -androstane-3 α ,17 β -diol or 3α -diol). The corresponding neurosteroidogenic enzymes are shown in italics adjacent to each reaction. as the peripheral benzodiazepine receptor (19) . Here, mito- yield allopregnanolone and THDOC, respectively. In addi- chondrial cholesterol side-chain cleavage enzyme (cyto- tion, androstanediol, another potent positive modulator α α chrome P450scc) catalyzes a side chain cleavage to convert of GABAA Rs, also utilizes the 5 -reductase/3 -HSD meta- cholesterol into pregnenolone, an important rate-limiting bolic pathway to catalyze its synthesis from testosterone step for the production of allopregnanolone and THDOC. (3, 9) (Figure 1). Pregnenolone is then converted by 3 β -hydroxysteroid The steroidogenic enzymes are not uniformly distri- dehydrogenase (3 β -HSD) into progesterone with further buted throughout the brain but are localized in specific metabolism of progesterone by 21 hydroxylase (p450c21), brain regions and cell types (20) . Cytochrome p450scc, yielding deoxycorticosterone. Finally, progesterone and for example, is expressed in both principal neurons and deoxycorticosterone are metabolized by 5 α -reductase fol- glial cells in various brain regions including the amyg- lowed by 3 α -hydroxysteroid dehydrogenase (3 α -HSD), to dala, hypothalamus, thalamus, cortex, and hippocampus G. MacKenzie and J. Maguire: Neurosteroids and GABAergic signaling 31 (21) . Furthermore, both 5 α -reductase protein and 3 α -HSD by the 5 α -reductase inhibitor, finasteride (23, 26, 27, 31) . mRNA have been shown to colocalize in principal neurons Allopregnanolone is also found at low nanomolar concen- in the thalamus, striatum, cerebellum, cortex, amygdala, trations in the plasma of both humans (32, 33) and rats and hippocampus, indicating that these are likely sites of (34 – 36) and fluctuates in response to stress (23, 36, 37) neurosteroidogenesis (22) . However, there is limited or no stage of menstrual/estrous cycle (32, 38) and pregnancy expression in interneurons with weak 5 α -reductase/3 α - (33, 37, 39 – 41) , reflecting changes in peripheral progester- HSD expression found only in the granule cells of the one levels. During pregnancy, plasma allopregnanolone cerebellum and olfactory bulb (22) . As neurosteroids are levels have been shown to reach concentrations ranging > produced in the same neurons that express GABAA Rs, they from 40 n m to 100 n m in both rats (35) and humans (33, may act in an autocrine as well as a paracrine fashion to 37, 39 – 41) . Similarly, allopregnanolone levels have been alter neuronal excitability. Interestingly, p450c21 mRNA shown to increase during pregnancy in the rat cerebral has so far only been found in the brain stem and at very cortex, peaking by day 19 and returning to control levels low levels in the cerebellum, suggesting that local meta- upon parturition (day 21) (35) . It is important to note that bolism of steroid hormone precursors from the periphery although basal and peak neurosteroids levels have been might be the prominent pathway for neuronal THDOC syn- detected at nanomolar concentrations under normal thesis, which coincides with the observation that THDOC physiological circumstances, these concentrations are is not detectable in the brains of adrenalectomized sufficient to positively modulate GABAA Rs. Further, neu- animals (20, 23) . Indeed, because steroid hormones are rosteroid concentrations may be significantly higher at small and lipophilic, peripherally derived hormones from specific neuronal locations reflecting local synthesis, dif- the adrenal cortex, placenta, or gonads can readily cross fusion barriers, and metabolism. the blood-brain barrier and plasma membrane, where Although neurosteroid concentration measurements they can be locally metabolized into neurosteroids (24) . It have been made in the central nervous system (CNS) of has also been observed that some steroidogenic enzymes both rats (23, 35, 36, 42, 43) and humans (44 – 46) , accu- are found in more than one subcellular compartment. For rately measuring neurosteroid concentrations is difficult instance, cytochrome p450c17, an important enzyme in the and reflected in the range of neurosteroid concentrations pathway that mediates the conversion of pregnanolone reported in the literature. Radioimmunoassays are com- into DHEAS and androstenediol, is found in the cell body, monly used to measure neurosteroid levels and are highly axon, and dendrites of embryonic basal ganglia and cer- sensitive. However, sample contamination,