Review
Neurosteroid biosynthesis: Enzymatic pathways and neuroendocrine regulation by neurotransmitters and neuropeptides

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Abstract

Neuroactive steroids synthesized in neuronal tissue, referred to as neurosteroids, are implicated in proliferation, differentiation, activity and survival of nerve cells. Neurosteroids are also involved in the control of a number of behavioral, neuroendocrine and metabolic processes such as regulation of food intake, locomotor activity, sexual activity, aggressiveness, anxiety, depression, body temperature and blood pressure. In this article, we summarize the current knowledge regarding the existence, neuroanatomical distribution and biological activity of the enzymes responsible for the biosynthesis of neurosteroids in the brain of vertebrates, and we review the neuronal mechanisms that control the activity of these enzymes. The observation that the activity of key steroidogenic enzymes is finely tuned by various neurotransmitters and neuropeptides strongly suggests that some of the central effects of these neuromodulators may be mediated via the regulation of neurosteroid production.

Introduction

It is firmly established that steroid hormones play a crucial role in the development and functioning of the central nervous system (CNS) [60], [140], [218], [239], [240], [332], [338], [442], [467], [468], [469], [470], [593], [654], [656], [743], [825]. Depending on their chemical structure and plasma concentrations, steroids can exert either protective or adverse effects on neural tissues [120], [121], [122], [167], [223], [253], [348], [382], [471], [481], [662], [682], [687], [712], [713], [714], [843], [844], [845]. It has long been thought that steroidogenic glands, including the adrenal cortex, gonads and placenta, were the only sources of steroids that could act on the brain. However, seminal observations made by the group of Baulieu and Robel have shown that this view is incorrect. First, these authors discovered that the concentration of several steroids, notably pregnenolone (Δ5P), dehydroepiandrosterone (DHEA) and their sulfate esters Δ5P sulfate (Δ5PS) and DHEA sulfate (DHEAS), are much higher in the brain than in the plasma [55], [151], [152]. Second, they showed that the levels of these steroids in brain tissue remain elevated long after adrenalectomy and castration [125], [151], [152]. Third, they found that the circadian variations of steroid concentrations in brain tissue are not synchronized with those of circulating steroids [624]. These observations led them to propose that the brain could actually synthesize biologically active steroids, and they coined the term “neurosteroids” to designate these brain-born neuroactive steroids [57], [58], [623], [626].

The concept of neurosteroidogenesis has been subsequently substantiated by two sets of observations. (i) The occurrence of steroidogenic enzymes or their mRNAs has been evidenced, respectively, by immunohistochemistry or in situ hybridization studies, either in neurons or in glial cells, depending on the species and the enzyme considered [486], [487], [492], [493], [494], [495], [524], [623], [625], [626], [720], [745], [782], [792]. (ii) The corresponding enzymatic activities were demonstrated through the ability of brain tissue to convert tritiated precursors such as cholesterol or 5P into radioactive metabolites including 7α-hydroxypregnenolone (7αΟΗ-Δ5P), 17-hydroxypregnenolone (17OH-5P), progesterone (P), 17-hydroxyprogesterone (17OH-P), DHEA, 7α-hydroxydehydroepiandrosterone (7αOH-DHEA), dihydroprogesterone (DHP), tetrahydroprogesterone (THP, allopregnanolone), Δ5PS and DHEAS [54], [61], [141], [177], [304], [325], [454], [455], [456], [486], [492], [493], [494], [495], [775], [779], [780], [781], [785], [792], [793].

Concurrently, it became clear that neurosteroids exert a large array of biological activities in the brain [65], [382], [431], [568], [739] either through a conventional genomic action or through interaction with membrane receptors. In particular, neurosteroids have been found to act as allosteric modulators of the GABAA/central-type benzodiazepine receptor complex [64], [65], [156], [380], [431], NMDA receptors [317], [436], [448], [449], [485], [513], kainate receptors [154], [181], AMPA receptors [181], [648], [649], sigma receptors [278], [459], [460], [461], [462], [512], [738], [746], [796], glycine receptors [63], [78], [322], [432], [508], [850], serotonin receptors [366], [693], [694], nicotinic receptors [20], [101], [561], [584], [800] and muscarinic receptors [295], [358], [725]. More recently, it has been found that neurosteroids may directly activate G protein-coupled membrane receptors [205], [274], [279], [421], [500], [552], [667], [751], [790], [791], [876], [877] or indirectly modulate the binding of neuropeptides to their receptors [252], [414], [742], [768], [884]. Finally, neurosteroids have been shown to bind to microtubule-associated protein 2 and to stimulate tubulin polymerization in cultured neurons [310], [390], [526], [597].

In vivo studies also indicate that neurosteroids are involved in the regulation of various neurophysiological and behavioral processes, including cognition, arousal, stress, depression, anxiety and sleep, as well as in sexual- and feeding-related behaviors and locomotion [57], [83], [158], [180], [181], [182], [191], [208], [209], [264], [431], [463], [464], [489], [490], [501], [509], [594], [614], [683], [726], [739], [804], [805], [808]. Paradoxically, in spite of the evidence that locally produced steroids play a major role as signaling molecules within the brain, to date, little is known regarding the neural mechanisms regulating neurosteroid biosynthesis in the CNS. However, recent studies performed mainly in amphibians and birds have shown that the production of neurosteroids is finely regulated by neurotransmitters and neuropeptides.

The aim of the present review is to summarize the current knowledge regarding the distribution of steroidogenic enzymes, the biosynthesis of endogenous steroids and the regulation of their production in the CNS of vertebrates.

Section snippets

Neurosteroid biosynthesis in the vertebrate brain

The main criterion supporting the concept of neurosteroidogenesis is based upon the occurrence of biologically active steroidogenic enzymes in neural tissues. The presence of several key steroidogenic enzymes has now been demonstrated in the brain of vertebrates by immunohistochemistry and/or in situ hybridization (Table 1). These include the steroidogenic acute regulatory protein (StAR), cytochrome P450 side-chain cleavage (P450scc), 3β-hydroxysteroid dehydrogenase/Δ5–Δ4 isomerase (3β-HSD),

Regulation of neurosteroid biosynthesis by neurotransmitters and neuropeptides

As indicated above, it is now firmly established that, in all classes of vertebrates, the brain has the capability of synthesizing de novo biologically active steroids from cholesterol. There is also clear evidence that these brain-born steroids play important roles in the control of behavioral and neurophysiological processes such as learning, stress, anxiety, depression, sleep, sexual activity and food consumption. Surprisingly, however, in mammals, little is known regarding the neuronal

Unresolved issues and future perspectives

The basic observation that certain biologically active steroids are present in higher concentrations in the CNS than in blood, made by the group of Baulieu almost three decades ago [55], [151], [152], has been a major breakthrough. Since then, most enzymes responsible for the biosynthesis of steroids have been localized in the brain of many representative species of vertebrates (Table 1), and the occurrence of the corresponding enzymatic activities in brain tissue has been demonstrated.

Acknowledgments

This work was supported by grants from the Institut National de la Santé et de la Recherche Médical (Inserm U413), The Ministère des Affaires Etrangères (France-Québec exchange Program No. PV-P-73-9 to G.P. and H.V.), a France-Québec exchange program (Inserm-Fonds de la Recherche en Santé du Québec, FRSQ to G.P. and H.V.), France–Korean exchange programs (Inserm-Korea Science and Engineering Foundation, KOSEF to J.Y.S. and H.V.; and Science and Technology Amical Research, STAR to J.L.D.R.,

References (884)

  • N. Aste et al.

    Distribution and effects of testosterone on aromatase mRNA in the quail forebrain: a non-radioactive in situ hybridization study

    J. Chem. Neuroanat.

    (1998)
  • N. Aste et al.

    Forebrain Fos responses to reproductively related chemosensory cues in aromatase knockout mice

    Brain Res. Bull.

    (2003)
  • T. Azuma et al.

    Neurosteroids in cerebrospinal fluid in neurologic disorders

    J. Neurol. Sci.

    (1993)
  • M. Baillien et al.

    A direct dopaminergic control of aromatase activity in the quail preoptic area

    J. Steroid Biochem. Mol. Biol.

    (1997)
  • J. Bakker et al.

    Sexual partner preference requires a functional aromatase (cyp19) gene in male mice

    Horm. Behav.

    (2002)
  • J. Balthazart et al.

    Immunocytochemical localization of aromatase in the brain

    Brain Res.

    (1990)
  • J. Balthazart

    Testosterone metabolism in the avian hypothalamus

    J. Steroid Biochem. Mol. Biol.

    (1991)
  • J. Balthazart et al.

    Neuroanatomical specificity in the autoregulation of aromatase-immunoreactive neurons by androgens and estrogens: an immunocytochemical study

    Brain Res.

    (1992)
  • J. Balthazart

    Steroid control and sexual differentiation of brain aromatase

    J. Steroid Biochem. Mol. Biol.

    (1997)
  • J. Balthazart et al.

    Phosphorylation processes mediate rapid changes of brain aromatase activity

    J. Steroid Biochem. Mol. Biol.

    (2001)
  • J. Balthazart et al.

    Interactions between aromatase (estrogen synthase) and dopamine in the control of male sexual behavior in quail

    Comp. Biochem. Physiol.

    (2002)
  • M.L. Barbaccia et al.

    Isoniazid-induced inhibition of GABAergic transmission enhances neurosteroid content in the rat brain

    Neuropharmacology

    (1996)
  • M.L. Barbaccia et al.

    Stress and neurosteroids in adult and aged rats

    Exp. Gerontol.

    (1998)
  • M.L. Barbaccia et al.

    Clozapine, but not haloperidol, increases brain concentrations of neuroactive steroids in the rat

    Neuropsychopharmacology

    (2001)
  • S.W. Barth et al.

    Localization of arginine vasotocin (AVT) mRNA in extrasomal compartments of magnocellular neurons in the chicken hypothalamo-neurohypophysial system

    Comp. Biochem. Physiol. B Biochem. Mol. Biol.

    (2000)
  • H.C. Bauer et al.

    Micromethod for the determination of 3β-HSD activity in cultured cells

    J. Steroid Biochem.

    (1989)
  • E.E. Baulieu

    Steroid hormones in the brain: several mechanisms?

  • E.E. Baulieu

    Neurosteroids: a new function in the brain

    Biol. Cell

    (1991)
  • E.E. Baulieu

    Neurosteroids: a novel function of the brain

    Psychoneuroendocrinology

    (1998)
  • D. Belelli et al.

    The interaction of general anaesthetics and neurosteroids with GABAA and glycine receptors

    Neurochem. Int.

    (1999)
  • D. Belelli et al.

    Neuroactive steroids and inhibitory neurotransmission: mechanisms of action and physiological relevance

    Neuroscience

    (2006)
  • S. Beyenburg et al.

    Expression of mRNAs encoding for 17β-hydroxysteroid dehydrogenase isozymes 1, 2, 3 and 4 in epileptic human hippocampus

    Epilepsy Res.

    (2000)
  • C. Beyer et al.

    Aromatase-immunoreactivity is localised specifically in neurones in the developing mouse hypothalamus and cortex

    Brain Res.

    (1994)
  • C. Beyer et al.

    Aromatase-immunoreactive neurons in the adult female chicken brain detected using a specific antibody

    Brain Res. Bull.

    (1994)
  • T. Bíró et al.

    Allosteric modulation of glycine receptors is more efficacious for partial rather than full agonists

    Neurochem. Int.

    (2004)
  • M. Blázquez et al.

    Cloning, sequence analysis, tissue distribution, and sex-specific expression of the neural form of P450 aromatase in juvenile sea bass (Dicentrarchus labrax)

    Mol. Cell. Endocrinol.

    (2004)
  • R.W. Bonsall et al.

    Identification of radioactivity in cell nuclei from brain, pituitary gland and genital tract of male rhesus monkeys after the administration of [3H]testosterone

    J. Steroid Biochem.

    (1989)
  • J. Bormann

    Electrophysiological characterization of diazepam binding inhibitor (DBI) on GABAA receptors

    Neuropharmacology

    (1991)
  • J.C. Bournat et al.

    Regulation of the Y1 neuropeptide Y receptor gene expression in PC12 cells

    Mol. Brain Res.

    (2001)
  • S.K. Boyd

    Arginine vasotocin facilitation of advertisement calling and call phonotaxis in bullfrogs

    Horm. Behav.

    (1994)
  • S.K. Boyd

    Brain vasotocin pathways and the control of sexual behaviors in the bullfrog

    Brain Res. Bull.

    (1997)
  • I.G. Abbaszade et al.

    Isolation of a new mouse 3β-hydroxysteroid dehydrogenase isoform, 3β-HSD VI, expressed during early pregnancy

    Endocrinology

    (1997)
  • S.E. Abdelgadir et al.

    Distribution of aromatase cytochrome P450 messenger ribonucleic acid in adult rhesus monkey brains

    Biol. Reprod.

    (1997)
  • S. Acharjee et al.

    Molecular cloning pharmacological characterization and histochemical distribution of frog vasotocin and mesotocin receptors

    J. Mol. Endocrinol.

    (2004)
  • R.C. Agís-Balboa et al.

    Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis

    Proc. Natl. Acad. Sci. USA

    (2006)
  • Y. Akwa et al.

    Neurosteroid metabolism: 7α-hydroxylation of dehydroepiandrosterone and pregnenolone by rat brain microsomes

    Biochem. J.

    (1992)
  • Y. Akwa et al.

    Astrocytes and neurosteroids: metabolism of pregnenolone and dehydroepiandrosterone. Regulation by cell density

    J. Cell. Biol.

    (1993)
  • H. Alho et al.

    Cellular and subcellular localization of an octadecaneuropeptide derived from diazepam binding inhibitor: immunohistochemical studies in the rat brain

    J. Chem. Neuroanat.

    (1989)
  • R.R. Anholt et al.

    Peripheral-type benzodiazepine receptors in the central nervous system: localization to olfactory nerves

    J. Neurosci.

    (1984)
  • S. Andersson et al.

    Structural and biochemical properties of cloned and expressed human and rat steroid 5α-reductases

    Proc. Natl. Acad. Sci. USA

    (1990)
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    Part of this review has been presented as the Geoffrey Harris Prize for Neuroendocrinology, Budapest, 2007.

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