Endocrinology, doi:10.1210/en.2007-1592
Endocrinology Vol. 149, No. 6 2757-2761
Copyright © 2008 by The Endocrine Society
Progesterone Biosynthesis and Action in the Developing Neuron
Kazuyoshi Tsutsui
Laboratory of Integrative Brain Sciences, Department of Biology, Faculty of Education and Integrated Arts and Sciences, Waseda University, Shinjuku-ku, Tokyo 169-8050, Japan
Address all correspondence and requests for reprints to: Kazuyoshi Tsutsui, Ph.D., Professor, Laboratory of Integrative Brain Sciences, Department of Biology, Faculty of Education and Integrated Arts and Sciences, Waseda University, 1-6-1 Nishi-Waseda, Shinjuku-ku, Tokyo 169-8050, Japan. E-mail: k-tsutsui{at}waseda.jp.
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Abstract
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The brain has traditionally been considered to be a target site of peripheral steroid hormones. By contrast, new findings over the past decade have shown that the brain itself also has the capability of forming steroids de novo, the so-called neurosteroids. De novo neurosteroidogenesis in the brain from cholesterol is a conserved property of vertebrates. When understanding the action of neurosteroids in the brain, data on the regio- and temporal-specific synthesis of neurosteroids are needed. Recently the Purkinje cell, an important brain neuron, has been identified as a major site for neurosteroid formation in vertebrates. This is the first demonstration of de novo neuronal neurosteroidogenesis in the brain. This discovery has allowed deeper insights into neuronal progesterone formation and organizing actions of progesterone have become clear by the studies using the Purkinje cell as an excellent cellular model, which is known to play an important role in memory and learning processes. In mammals, the Purkinje cell actively synthesizes progesterone de novo from cholesterol during neonatal life when cerebellar neuronal circuit formation occurs. Progesterone promotes dendritic growth, spinogenesis, and synaptogenesis via its nuclear receptor in the developing Purkinje cell. Such organizing actions may contribute to the formation of cerebellar neuronal circuit during neonatal life. Allopregnanolone, a progesterone metabolite, is also synthesized in the cerebellum and acts on Purkinje cell survival in the neonate. This paper summarizes the advances made in our understanding of progesterone formation and metabolism and actions of progesterone and its metabolite in the developing neuron.
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Introduction
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STEROID HORMONES SUPPLIED by the peripheral steroidogenic glands act on brain tissues through intracellular receptor-mediated mechanisms to regulate several important brain neuronal functions during development that persist into adulthood in vertebrates. Therefore, the brain has traditionally been considered to be a target site of peripheral steroid hormones. By contrast, new findings over the past decade have shown that the brain itself also has the capability of forming steroids de novo from cholesterol, the so-called neurosteroids (for reviews, see Refs. 1, 2, 3, 4, 5). The formation of neurosteroids in the brain was originally demonstrated in mammals and subsequently in other vertebrates, such as birds, amphibians, and fish (for reviews, see Refs. 1, 2, 3, 4, 5). Thus, de novo neurosteroidogenesis in the brain from cholesterol is a conserved property of vertebrates.
To analyze neurosteroid biosynthesis and action in the brain, it is necessary to know which neurosteroids are synthesized in specific brain regions at specific times in development. Such information is essential to develop hypotheses predicting the potential roles of those neurosteroids in the developing and adult brains. Thus, the studies for this exciting area of neurohormonal research should be focused on the biosynthesis and action of neurosteroids produced locally in the identified neurosteroidogenic cells underlying important brain functions. The oligodendrocyte was first accepted to be the primary site for neurosteroid formation in the brain (for reviews, see Refs. 1 and 4). Subsequently astrocytes (6) and some neurons (7) were shown to express some steroidogenic enzymes. However, whether neurons located in the brain produce neurosteroids remained unclear. Recently we demonstrated that the Purkinje cell, an important brain neuron, is a major site for neurosteroid formation in a variety of vertebrates (8, 9, 10, 11, 12, 13, 14, 15). This is the first demonstration of de novo neuronal neurosteroidogenesis in the brain.
Our studies on mammals using the Purkinje cell have provided the opportunity to understand neuronal neurosteroidogenesis. Interestingly, this neuron possesses several kinds of steroidogenic enzymes, such as cytochrome P450 side-chain cleavage enzyme (P450scc) and 3β-hydroxysteroid dehydrogenase/
5-4-isomerase (3β-HSD), and actively produces progesterone during neonatal life, when cerebellar neuronal circuit formation occurs (10, 11, 16) (Fig. 1
). Allopregnanolone, a progesterone metabolite, is also synthesized in the neonatal cerebellum (17, 18, 19, 20). Subsequently important actions of progesterone (21, 22, 23, 24) and the progesterone metabolite allopregnanolone (25) have become clear by the studies on mammals using the Purkinje cell as an excellent cellular model, which is known to play an essential role in the process of memory and learning. Furthermore, this neuron expresses a key enzyme of estrogen formation, cytochrome P450 aromatase (P450arom), and produces estradiol in the neonate (15, 18). Estradiol also contributes to important events in the developing Purkinje cell (15, 26).
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FIG. 1. Biosynthesis and organizing actions of progesterone in the developing Purkinje cell. The Purkinje cell is a major site for neurosteroid formation in the brain. The rat Purkinje cell expresses several kinds of steroidogenic enzymes and produces pregnenolone and progesterone. The expression of P450scc remains during neonatal development and in adulthood, indicating the constant production of pregnenolone and its sulfate. This neuron also produces actively progesterone due to an increase of 3β-HSD activity only during neonatal life. Progesterone acts on the Purkinje cell through intracellular receptor-mediated mechanisms that promote dendritic growth, spinogenesis, and synaptogenesis in this neuron by genomic mechanisms. Thus progesterone produced in the Purkinje cell may mediate its actions through an intracrine mechanism. Progesterone may induce the expression of some neurotrophic factors that directly promote Purkinje dendritic growth, spinogenesis, and synaptogenesis during neonatal life. PRE, Progesterone response element.
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Progesterone Formation and Metabolism
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Progesterone is known to be a sex steroid and acts on brain tissues through nuclear progesterone receptors. In contrast to this classical concept, the new concept of de novo progesterone formation from cholesterol in the brain neuron derived from our observations made in the 1990s.
Pregnenolone is a precursor of progesterone secreted by peripheral steroidogenic glands and the formation of pregnenolone is initiated by the cleavage of the cholesterol side chain by cytochrome P450scc, a rate-limiting mitochondrial enzyme. Therefore, it is essential to demonstrate the formation of pregnenolone in the brain neuron. The first immunohistochemical study in quail using an antibody against P450scc reported that the striking observation of the distribution of intense immunoreactive cells in the cerebellar cortex (8, 9). The distribution of immunoreactive cell bodies and fibers was coincident with the location of somata and dendrites of Purkinje cells (8, 9). Western immunoblot analysis confirmed the presence of P450scc in Purkinje cells (8, 9). These avian findings provided the first evidence for the neuronal location of cytochrome P450scc. We extended these findings further and investigated the presence of P450scc in rat Purkinje cells (10). An antibody against inositol triphosphate receptor, a marker of the Purkinje cell, recognized P450scc-immunoreactive cerebellar cells that showed no immunoreaction with glial fibrillary acidic protein, a specific marker of astrocytes (10). Thus, immunoreaction with P450scc antibody was confined to the somata and dendrites of Purkinje cells in the rat cerebellum (10). Interestingly, P450scc appeared in the rat Purkinje cell immediately after its differentiation, and the expression of this enzyme persisted during neonatal development into adulthood, indicating that Purkinje cells may produce pregnenolone throughout life (10). In addition to higher vertebrates, our recent studies further identified P450scc in the Purkinje cell of amphibians (12). Taken together, these findings obtained in both higher and lower vertebrates indicate that Purkinje cells possess P450scc and produce pregnenolone (Fig. 1
). In addition, steroidogenic acute regulatory protein (StAR) was found in Purkinje cells (16) (Fig. 1). StAR is involved in the transport of cholesterol to the inner mitochondrial membrane, in which P450scc is localized, and thus plays a key role in acute steroid biosynthesis in peripheral steroidogenic glands (27). StAR may also contribute to the regulation of pregnenolone formation in the Purkinje cell (Fig. 1).
Because the biosynthesis of progesterone from pregnenolone is performed by 3β-HSD, the demonstration of the expression of 3β-HSD in the Purkinje cell is therefore essential to establish the concept of de novo progesterone formation from cholesterol in this neuron. We have further demonstrated that Purkinje cells express not only P450scc but also 3β-HSD (Fig. 1). RT-PCR and biochemical analyses showed the expression of 3β-HSD and its enzymatic activity in the rat cerebellum (11). Using in situ hybridization of 3β-HSD mRNA, the site of 3β-HSD expression was localized in Purkinje cells and external granule cells (11). Thus, both P450scc and 3β-HSD are expressed in Purkinje cells (Fig. 1). The colocalization of P450scc and 3β-HSD in external granule cells is still unclear. The expression of 3β-HSD in Purkinje cells was also evident in other vertebrates (2, 14). Surprisingly, the expression of 3β-HSD increased during neonatal life, unlike P450scc (10, 11). Such an age-dependent expression of 3β-HSD was confirmed by biochemical studies together with HPLC analysis, indicating an increase of progesterone formation during neonatal life (11) (Fig. 1). Thus, this neuron actively produces progesterone as a product of an increase of 3β-HSD activity during neonatal life (11) (Fig. 1).
Biochemical analysis together with HPLC and thin-layer chromatography further revealed that the progesterone metabolite allopregnanolone is also found in the cerebellum during neonatal life (17, 18, 19, 20). Thus, 5
-reductase and 3-HSD metabolize some of progesterone to allopregnanolone in the cerebellum during development.
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Organizing Actions of Progesterone
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Because the Purkinje cell is a major site for progesterone formation and metabolism in the brain, this neuron has also served as an excellent cellular model for the study of actions of these neurosteroids. In mammals, this neuron actively produces progesterone during neonatal life, when cerebellar neuronal circuit formation occurs (10, 11, 16). Because this discovery of regio- and temporal-specific progesterone synthesis, organizing actions of progesterone have been demonstrated by the studies on mammals using the Purkinje cell.
Purkinje cells actively synthesize progesterone during the neonatal period, as the expression of 3β-HSD and its enzymatic activity increase in neonatal rats (11) (Fig. 1). Allopregnanolone, a progesterone metabolite, is also synthesized in the cerebellum of neonatal rats (17, 18, 19, 20) (Fig. 1). It is well known that in the rat marked morphological changes occur in the cerebellum after birth during neonatal life. According to Altman (28, 29), rat Purkinje cells differentiate just after birth, and the formation of the cerebellar cortex becomes complete in the neonate through the processes of migration of external granule cells, neuronal and glial growth, and synaptogenesis. Thus, postnatal development in the cerebellum is dramatic during neonatal life when cerebellar progesterone and allopregnanolone concentrations are high (11, 17, 18). Therefore, progesterone and/or allopregnanolone may be involved in the formation of the cerebellar neuronal circuit that occurs during neonatal life by promoting neuronal growth and neuronal synaptic contact.
To test this hypothesis, we examined the effects of progesterone and allopregnanolone, produced as neurosteroids in the Purkinje cell during neonatal life on neuronal growth, spinogenesis, and synaptogenesis in the rat cerebellum. In vitro studies using cultured cerebellar slices of newborn rats showed that progesterone promotes dendritic growth and dendritic spine formation of the Purkinje cell (21, 22) (Fig. 1). A similar result was obtained by in vivo studies (21, 22). Electron microscopic analysis further revealed that progesterone induces an increase of the density of synapses on the Purkinje cell (21, 22) (Fig. 1). These effects were blocked by the progesterone receptor antagonist mifepristone (RU486) (21, 22). In contrast to progesterone, there was no significant effect of allopregnanolone on these aspects of Purkinje development (21, 22). These results indicate that progesterone promotes the dendritic growth, spinogenesis, and synaptogenesis of Purkinje cells.
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Mode of Action and Functional Significance of Progesterone
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To understand the mode of action of progesterone, the expression of progesterone receptor (PR) in the cerebellum was then characterized in neonatal rats. Interestingly, intranuclear PR-A and PR-B were expressed in the Purkinje cell (21, 22, 23) (Fig. 1). It is therefore considered that progesterone acts directly on Purkinje cells through intranuclear receptor-mediated mechanisms to promote Purkinje dendritic growth, spinogenesis, and synaptogenesis (21, 22, 23) (Fig. 1). Such genomic actions of progesterone may be essential for the formation of the cerebellar neuronal circuit during neonatal development.
On the other hand, Purkinje cells express the putative membrane PR, 25-Dx, during neonatal life (30). RT-PCR and Western immunoblot analyses revealed the expressions of 25-Dx and its mRNA in the rat cerebellum, which increased during neonatal life (30). By immunocytochemistry, the expression of 25-Dx was localized in the Purkinje cell and external granule cell layer (30). Therefore, progesterone may promote dendritic growth, spinogenesis, and synaptogenesis via 25-Dx as well as its nuclear receptor in the Purkinje cell in the neonate. Future study is needed to demonstrate whether the promotion of Purkinje dendritic growth, spinogenesis, and synaptogenesis by progesterone is due to both genomic and nongenomic actions.
The formation of the cerebellar neuronal circuit occurs during neonatal life. A series of our studies indicate that progesterone promotes Purkinje dendritic growth, spinogenesis, and synaptogenesis. Such organizing actions may contribute to the formation of the cerebellar neuronal circuit during neonatal life. Neurotrophins are attractive candidate regulators of Purkinje dendrite and spine development. It has been reported that neurotrophic factors, such as brain-derived neurotrophic factor and neurotrophin-3, are highly expressed in the developing cerebellum and are critical for proper development of Purkinje cells and granule cells (31, 32, 33). Therefore, progesterone may induce the expression of some neurotrophic factors that directly promote Purkinje dendritic growth, spinogenesis, and synaptogenesis during neonatal life.
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Neuroprotective Actions of Progesterone and Allopregnanolone
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In addition to organizing actions of progesterone as described above, it has been reported that mifepristone (RU486), an antiprogesterone protects Purkinje cells from developmental cell death (24). Because this protective effect of RU486 is considered to be independent on the activation of nuclear PRs (24), 25-Dx-mediated mechanisms might also be involved in the protection of Purkinje cells.
Purkinje cells metabolize some of progesterone to allopregnanolone during neonatal life (17, 18, 19, 20). Although allopregnanolone failed to promote the dendritic growth, spinogenesis, and synaptogenesis of Purkinje cells (21, 22), it has been shown that allopregnanolone is involved in Purkinje and granule cell survival (25). The Niemann-Pick type C (NP-C) mouse has been used as an excellent animal model for understanding allopregnanolone action. NP-C is an autosomal recessive, childhood neurodegenerative disease characterized by defective intracellular cholesterol trafficking, resulting in Purkinje cell degeneration as well as neuronal degeneration in other regions. Brains from adult NP-C mice contain less allopregnanolone than wild-type brain (25). Administration of allopregnanolone to neonatal NP-C mice increases Purkinje cell survival and delays neurodegeneration (25).
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Related Findings
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Estradiol is also known to be a sex steroid and acts on brain tissues. Recently we further demonstrated the expression of P450arom, a key enzyme of estrogen formation, in Purkinje cells of neonatal rats (15). RT-PCR-Southern and in situ hybridization analyses showed that the expression of P450arom mRNA in the cerebellum is restricted to Purkinje cells and external granule cells in neonatal rats (15). A specific enzyme immunoassay for estradiol further indicated that cerebellar estradiol concentrations in the neonate are higher than those in prepubertal and adult rats. Thus, Purkinje cells may also synthesize estradiol during the neonatal period. Interestingly, estradiol also promotes the dendritic growth, spinogenesis, and synaptogenesis of Purkinje cells (15, 26). Because Purkinje cells express estrogen receptor-β in the neonatal rat (34), it is likely that estradiol acts directly on Purkinje cells through intranuclear estrogen receptor-β-mediated mechanisms to promote dendritic growth, spinogenesis, and synaptogenesis in Purkinje cells during development (15, 26). Our recent study has demonstrated that estradiol induces dendritic growth, spinogenesis, and synaptogenesis in the developing Purkinje cell via brain-derived neurotrophic factor action during neonatal life (26).
In addition to Purkinje cells, the localization of neurosteroidogenic enzymes in other brain neurons has further characterized (35, 36). In the rat hippocampus, the localization of cytochrome P450scc, P450c17, and P450arom has been found in pyramidal neurons in the CA1-CA3 regions as well as granule cells in the dentate gyrus (35, 36). Thus, neurons as well as glial cells are now considered to play a major role in neurosteroid formation and metabolism in the brain. In addition to these brain neurons, cytochrome P450scc expression has been reported in neurons in the retinal ganglion, sensory neurons in the dorsal root ganglia, and motor neurons in the spinal cord of the rat (7, 37).
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Conclusions
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The Purkinje cell is a major site for progesterone formation and metabolism in the brain. This brain neuron actively synthesizes progesterone de novo from cholesterol during neonatal life when cerebellar neuronal circuit formation occurs. Progesterone promotes Purkinje dendritic growth, spinogenesis, and synaptogenesis. The progesterone metabolite allopregnanolone is also involved in Purkinje and granule cell survival. Thus, the discovery of progesterone formation and metabolism in this brain neuron has opened avenues for a new research field in progesterone research. Future directions for this exciting area of research should focus on physiological roles of progesterone and allopregnanolone because Purkinje cells play an important role in the process of memory and learning. Therefore, behavioral studies using neurosteroidogenic enzyme knockout animals and electrophysiological studies on the occurrence of long-term potentiation and/or long-term depression are needed.
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Acknowledgments
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I thank Hirotaka Sakamoto, Mariko Usui, Hanako Shikimi, Katsunori Sasahara, Shogo Haraguchi, Minoru Takase, and Kazuyoshi Ukena for their work cited in this manuscript.
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Footnotes
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This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture, Japan (15207007, 16086206, and 18107002 to K.T.).
Disclosure Statement: The author has nothing to disclose.
First Published Online February 28, 2008
Abbreviations: 3β-HSD, 3β-Hydroxysteroid dehydrogenase/5-4-isomerase; NP-C, Niemann-Pick type C; P450arom, P450 aromatase; PR, progesterone receptor; P450scc, P450 side-chain cleavage enzyme; StAR, steroidogenic acute regulatory protein.
Received November 21, 2007.
Accepted for publication January 22, 2008.
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Abstract
Introduction
