ReviewBiosynthesis and action of neurosteroids
Introduction
The ever-growing field of neurosteroidogenesis began initially from the intersection of research in the neuropharmacology of ligand-gated ion channel receptors and research in steroid hormone synthesis. The demonstration that steroids could be synthesized de novo in the brain and the simultaneous experiments describing novel functions for certain steroidal compounds at nonclassical GABAA and NMDA receptors brought this new field to light. First, studies by Harrison and Simmonds and by Majewska demonstrated that certain steroids could modulate GABAA receptor function [31], [39]. They did so by increasing the duration and frequency of GABAA channel opening, via a site that was distinct from the GABA site. This action of steroids was mediated by progesterone derivatives, and the action of those derivatives was stereospecific [1], [2], [49], [51], [67]. Other steroids could also modulate GABA-ergic function, but rather than act as a positive modulator, these steroids acted as negative modulators and inhibited GABA-ergic function.
A parallel series of experiments by endocrinologists placed those neuroactive steroids directly at their site of action in the brain. The fact that steroids could be synthesized in the brain came initially from observations made in the 1980s by Baulieu and colleagues who found that steroids such as pregnenolone, DHEA and their sulfate and lipoidal esters were present in higher concentrations in tissue from the nervous system (brain and peripheral nerve) than in the plasma. While these compounds could be due to peripheral synthesis and then sequestration in the brain, Baulieu and colleagues found that the steroids remained in the nervous system long after gonadectomy or adrenalectomy [15], [16], suggesting that steroids could be synthesized de novo in the CNS and PNS. Such steroids were named ‘neurosteroids’ to refer to their unusual origin and to differentiate them from steroids derived from more classical steroidogenic organs such as gonads, adrenals and placentae.
Were these compounds synthesized in the brain or did they accumulate specifically in tissue from the nervous system? Several laboratories, including ours, determined directly if enzymes known to be involved in steroidogenesis, i.e. adrenals, gonads and placentae, could be responsible for neurosteroid synthesis (reviewed in [10], [44]). These studies have established unequivocally that the enzymes found in classic steroidogenic tissues are indeed found in the nervous system. Depending upon the steroid synthesized, these steroids could affect gene expression through action at classic intracellular nuclear receptors, or could affect neurotransmission through action at membrane ion-gated and other neurotransmitter receptors.
While it is now well known that neurosteroids can modulate neurotransmitter receptors, what is the consequence of this action, and does this differ between what occurs during development and in the adult? In the adult, neurosteroid stimulation of neurotransmitter receptors results in behavioral effects associated with those receptors: stimulation of GABAA receptors results in decreased anxiety [67], sedation [21], [56], [57], [58], and decreases in seizure activity [3], [19], [22], [23], [24], [47], [66]. Effects may also be mediated through other neurotransmitter receptors (reviewed in [10]). During development, neurosteroids have additional functions. Neurosteroids are involved in neuronal modeling, as DHEA and DHEAS stimulate embryonic axonal and dendritic growth, respectively [9], and allopregnanolone causes neurite regression [3]. Finally, there are effects of neurosteroids on neurotransmitter receptor expression, that ultimately affect the ability of the neurosteroids to mediate their effects [13], [14], [17], [18], [25], [59].
Since the enzymes that synthesize neurosteroids are the same as those that synthesize classic steroid hormones, we began studies aimed at determining if the transcriptional regulation of these genes was the same in classic steroidogenic tissues and in the nervous system. In addition, we have studied the regulation of neurosteroidogenic enzyme activity by selective serotonin reuptake inhibitors, and have also been using a mouse model of a neurodegenerative disease to study the roles of neurosteroids in development and maintenance of normal neuronal circuits.
Section snippets
Biosynthesis of neurosteroids
Steroid hormones are synthesized from cholesterol by a series of enzymes, both P450s and non-P450s, that act in concert to direct the synthesis of one or several distinct steroids in a particular cell. The determination of which steroid will be synthesized by a tissue depends, therefore, on the level of expression of a cohort of enzymes, and/or competition among enzymes for particular substrates. In the adrenals and gonads, the synthesis of androgens, estrogens, glucocorticoids and progestins
Action of neurosteroids on neuronal function
The sites of expression of the steroidogenic enzyme P450c17 indicated to us that products of this enzymatic activity, e.g. DHEA or DHEAS, may play a role in targeting thalamic axons to particular regions of the cortex during development. Hence, we sought to determine whether DHEA and DHEAS had an effect on embryonic cortical neurons [9]. We cultured neurons from the cortex of 16.5 day embryos, and determined directly if DHEA and DHEAS affected their morphology. We found that DHEA and DHEAS had
Transcriptional regulation of steroidogenic enzymes in the CNS
We have been studying the transcriptional regulation of two genes, P450scc and P450c17, and have identified different regions of these genes that are transcriptionally active in classic steroidogenic tissues vs. the brain (Fig. 4). The 5′ flanking DNA of the rat P450c17 gene has several transcriptionally active domains in adrenal and Leydig cells, as well as in neurons. In adrenals and Leydig cells, the transcription factor SF-1 plays a major role in the regulation of P450c17 [26], [69], [70].
Regulation of neurosteroidogenic enzyme activity
Studies by others indicated that neurosteroids may play a role in the etiology of some forms of depression. Initial studies in women with late luteal phase dysphoric disorder suggested that these women could be treated successfully for their depression with use of selective serotonin reuptake inhibitors (SSRIs) [60], [61], [62]. In other depressed patients, the levels of neurosteroids (specifically allopregnanolone) in the plasma [55] and cerebrospinal fluid [65] of patients, indicated that
Animal models for studying the function of neurosteroids
We have been using several animal models to study the endogenous function of neurosteroids in the development of the nervous system, including gene knock-outs and gene overexpression in transgenic mice. In addition, we have been using a mouse model of neurodegeneration, in which we believe that neurosteroids may play a role in the etiology of the disease. This mouse is a model for Niemann Pick Type C (NP-C) disease [48]. NP-C is an autosomal recessive neurodegenerative disease cause by
Acknowledgements
This work was supported by grants from The March of Dimes Birth Defects Foundation, The Ara Parseghian Medical Research Foundation, and by the NIH (HD27270) to SHM, by a grant from the NIH (NS01979) and the National Niemann Pick Foundation to LDG.
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