Abstract
The cerebellar cortex has been used as an excellent model to study synaptic formation and transmission of neural networks because it forms relatively simple neuronal networks compared to those of other brain regions. The formation of the mammalian cerebellar cortex becomes complete in the neonate through the processes of migration of external granule cells, neuronal and glial growth, and synaptogenesis. It is important to clarify the mechanism underlying synaptic formation of cerebellar neuronal networks during development. The brain has traditionally been considered to be a target site of peripheral steroid hormones. In contrast to this classical concept, new findings have shown that the brain has the capacity to synthesize steroids de novo from cholesterol, the so-called neurosteroids. In the middle 1990s, the Purkinje cell, a principal cerebellar neuron, was identified as a major site for neurosteroid formation in mammals as well as other vertebrates. This discovery has provided the opportunity to understand neuronal neurosteroidogenesis in the brain. In addition, biological actions of neurosteroids 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. Based on extensive studies on mammals over the past decade, it is considered that the Purkinje cell actively synthesizes progesterone and estradiol de novo from cholesterol during neonatal life, when cerebellar neuronal circuit formation occurs. Both progesterone and estradiol promote dendritic growth, spinogenesis, and synaptogenesis via each cognate nuclear receptor in the developing Purkinje cell. Such neurosteroid actions that may be mediated by neurotrophic factors contribute to the formation of cerebellar neuronal circuit during neonatal life. Allopregnanolone (3α,5α-tetrahydroprogesterone), a progesterone metabolite, is also synthesized in the cerebellum and acts on Purkinje cell survival in the neonate. This chapter summarizes the current knowledge regarding the biosynthesis and biological actions of neurosteroids in the cerebellum during development in terms of synaptic formation of cerebellar neuronal networks.
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References
Agís-Balboa RC, Pinna G, Zhubi A et al (2006) Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis. Proc Natl Acad Sci USA 103:14602–14607
Agís-Balboa RC, Pinna G, Pibiri F et al (2007) Down-regulation of neurosteroid biosynthesis in corticolimbic circuits mediates social isolation-induced behavior in mice. Proc Natl Acad Sci USA 104:18736–18741
Altman J (1972a) Postnatal development of the cerebellar cortex in the rat. I. The external germinal layer and the transitional molecular layer. J Comp Neurol 145:353–397
Altman J (1972b) Postnatal development of the cerebellar cortex in the rat. II. Phases in the maturation of Purkinje cells and of the molecular layer. J Comp Neurol 145:399–463
Altman J, Bayer SA (1978) Prenatal development of the cerebellar system in the rat. I. Cytogenesis and histogenesis of the deep nuclei and the cortex of the cerebellum. J Comp Neurol 179:23–48
Azcoitia I, Sierra A, Garcia-Segura LM (1999) Neuroprotective effects of estradiol in the adult rat hippocampus: interaction with insulin-like growth factor-I signaling. J Neurosci Res 58:815–822
Bates B, Rios M, Trumpp A et al (1999) Neurotrophin-3 is required for proper cerebellar development. Nat Neurosci 2:115–117
Baulieu EE (1997) Neurosteroids: of the nervous system, by the nervous system, for the nervous system (review). Rec Prog Horm Res 52:1–32
Baulieu EE, Robel P (1998) Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) as neuroactive neurosteroids. Proc Natl Acad Sci USA 95:4089–4091
Borghesani PR, Peyrin JM, Klein R et al (2002) BDNF stimulates migration of cerebellar granule cells. Development 129:1435–1442
Brake WG, Alves SE, Dunlop JC et al (2001) Novel target sites for estrogen action in the dorsal hippocampus: an examination of synaptic proteins. Endocrinology 142:1284–1289
Cahill MA (2007) Progesterone receptor membrane component 1: an integrative review. J Steroid Biochem Mol Biol 105:16–36
Carswell HVO, Dominiczak AF, Garcia-Segura LM et al (2005) Brain aromatase expression after experimental stroke: topography and time course. J Steroid Biochem Mol Biol 96:89–91
Carter AR, Chen C, Schwartz PM et al (2002) Brain-derived neurotrophic factor modulates cerebellar plasticity and synaptic ultrastructure. J Neurosci 22:1316–1327
Chan JR, Rodriguez-Waitkus PM, Ng BK et al (2000) Progesterone synthesized by Schwann cells during myelin formation regulates neuronal gene expression. Mol Biol Cell 11:2283–2295
Choi JM, Romeo RD, Brake WG et al (2003) Estradiol increases pre- and post-synaptic proteins in the CA1 region of the hippocampus in female rhesus macaques (Macaca mulatta). Endocrinology 144:4734–4738
Clark BJ, Wells J, King SR et al (1994) The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). J Biol Chem 269:28314–28322
Compagnone NA, Mellon SH (1998) Dehydroepiandrosterone: a potential signaling molecule for neocortical organization during development. Proc Natl Acad Sci USA 95:4678–4683
Compagnone NA, Mellon SH (2000) Neurosteroids: biosynthesis and function of these novel neuromodulators (review). Front Neuroendocrinol 21:1–56
Compagnone NA, Bulfone A, Rubenstein JLR et al (1995) Steroidogenic enzyme P450c17 is expressed in the embryonic central nervous system. Endocrinology 136:5212–5223
Corpéchot C, Robel P, Axelson M et al (1981) Characterization and measurement of dehydroepiandrosterone sulfate in rat brain. Proc Natl Acad Sci USA 78:4704–4707
Corpéchot C, Synguelakis M, Talha S et al (1983) Pregnenolone and its sulfate ester in rat brain. Brain Res 270:119–125
Do-Rego JL, Seong JY, Burel D et al (2009) Neurosteroid biosynthesis: enzymatic pathways and neuroendocrine regulation by neurotransmitters and neuropeptides. Front Neuroendocrinol 30:259–301
Drake EB, Henderson VW, Stanczyk FZ et al (2000) Associations between circulating sex steroid hormones and cognition in normal elderly women. Neurology 54:599–603
Engmann L, Losel R, Wehling M et al (2006) Progesterone regulation of human granulosa/luteal cell viability by an RU486-independent mechanism. J Clin Endocrinol Metab 91:4962–4968
Ernfors P, Lee KF, Jaenisch R (1994) Mice lacking brain-derived neurotrophic factor develop with sensory deficits. Nature 368:147–150
Freking F, Nazairians T, Schlinger BA (2000) The expression of the sex steroid-synthesizing enzymes CYP11A1, 3β-HSD, CYP17, and CYP19 in gonads and adrenals of adult and developing zebra finches. Gen Comp Endocrinol 119:140–151
Frye CA, Walf AA (2008) Effects of progesterone administration and APPswe + PSEN1Δe9 mutation for cognitive performance of mid-aged mice. Neurobiol Learn Mem 89:17–26
Furukawa A, Miyatake A, Ohnishi T et al (1998) Steroidogenic acute regulatory protein (StAR) transcripts constitutively expressed in the adult rat central nervous system: colocalization of StAR, cytochrome P-450scc (CYP XIA1), and 3β-hydroxysteroid dehydrogenase in the rat brain. J Neurochem 71:2231–2238
Ghoumari AM, Dusart I, El-Etr M et al (2003) Mifepristone (RU486) protects Purkinje cells from cell death in organotypic slice cultures of postnatal rat and mouse cerebellum. Proc Natl Acad Sci USA 100:7953–7958
Gould E, Woolley CS, Frankfurt M et al (1990) Gonadal steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood. J Neurosci 10:1286–1291
Griffin LD, Gong W, Verot L et al (2004) Niemann-Pick type C disease involves disrupted neurosteroidogenesis and responds to allopregnanolone. Nat Med 10:704–711
Hao J, Rapp PR, Janssen WG et al (2007) Interactive effects of age and estrogen on cognition and pyramidal neurons in monkey prefrontal cortex. Proc Natl Acad Sci USA 104:11465–11470
Haraguchi S, Koyama T, Hasunuma I et al (2010) Prolactin increases the synthesis of 7α-hydroxypregnenolone, a key factor for induction of locomotor activity, in breeding male newts. Endocrinology 151:2211–2222
Hofer M, Pagliusi SR, Hohn A et al (1990) Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain. EMBO J 9:2459–2464
Hojo Y, Hattori TA, Enami T et al (2004) Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017α and P450 aromatase localized in neurons. Proc Natl Acad Sci USA 101:865–870
Honda S, Harada N, Ito S et al (1998) Disruption of sexual behavior in male aromatase-deficient mice lacking exons 1 and 2 of the cyp19 gene. Biochem Biophys Res Commun 252:445–449
Ikeda Y, Nagai A, Ikeda MA et al (2003) Sexually dimorphic and estrogen-dependent expression of estrogen receptor beta in the ventromedial hypothalamus during rat postnatal development. Endocrinology 144:5098–5115
Inai Y, Nagai K, Ukena K et al (2003) Seasonal changes in neurosteroids in the urodele brain and environmental factors inducing their changes. Brain Res 959:214–225
Jacobs DM, Tang MX, Stern Y et al (1998) Cognitive function in nondemented older women who took estrogen after menopause. Neurology 50:368–373
Jakab RL, Wong JK, Belcher SM (2001) Estrogen receptor β immunoreactivity in differentiating cells of the developing rat cerebellum. J Comp Neurol 430:396–409
Jo DH, Abdallah MA, Young J et al (1989) Pregnenolone, dehydroepiandrosterone, and their sulfate and fatty acid esters in the rat brain. Steroids 54:287–297
Klein R, Parada LF, Coulier F et al (1990) TrkB, a novel tyrosine protein kinase receptor expressed during mouse neural development. EMBO J 8:3701–3709
Koenig HL, Schumacher M, Ferzaz B et al (1995) Progesterone synthesis and myelin formation by Schwann cells. Science 268:1500–1503
Mathur C, Prasad VVK, Raju VS et al (1993) Steroids and their conjugates in the mammalian brain. Proc Natl Acad Sci USA 90:85–88
Matsunaga M, Ukena K, Tsutsui K (2001) Expression and localization of cytochrome P450 17α-hydroxylase/c17, 20-lyase in the avian brain. Brain Res 899:112–122
Matsunaga M, Ukena K, Tsutsui K (2002) Androgen biosynthesis in the quail brain. Brain Res 948:180–185
Matsunaga M, Ukena K, Baulieu EE et al (2004) 7α-Hydroxypregnenolone acts as a neuronal activator to stimulate locomotor activity of breeding newts by means of the dopaminergic system. Proc Natl Acad Sci USA 101:17282–17287
McDonnell DP, Clemm DL, Hermann T et al (1995) Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens. Mol Endocrinol 9:659–669
McEwen BS, Akama K, Alves S et al (2001) Tracking the estrogen receptor in neurons: implications for estrogen-induced synapse formation (review). Proc Natl Acad Sci USA 98:7093–7100
Mellon SH, Deschepper CF (1993) Neurosteroid biosynthesis: genes for adrenal steroidogenic enzymes are expressed in the brain. Brain Res 629:283–292
Mellon SH, Vaudry H (2001) Biosynthesis of neurosteroids and regulation of their synthesis (review). Int Rev Neurobiol 46:33–78
Mensah-Nyagan AG, Feuilloley M, Dupont E et al (1994) Immunocytochemical localization and biological activity of 3β-hydroxysteroid dehydrogenase in the central nervous system of the frog. J Neurosci 14:7306–7318
Mensah-Nyagan AG, Do-Rego JL, Feuilloley M et al (1996a) In vivo and in vitro evidence for the biosynthesis of testosterone in the telencephalon of the female frog. J Neurochem 67:413–422
Mensah-Nyagan AG, Feuilloley M, Do-Rego JL et al (1996b) Localization of 17β-hydroxysteroid dehydrogenase and characterization of testosterone in the brain of the male frog. Proc Natl Acad Sci USA 93:1423–1428
Mensah-Nyagan AG, Do-Rego JL, Beaujean D et al (1999) Neurosteroids: expression of steroidogenic enzymes and regulation of steroid biosynthesis in the central nervous system (review). Pharmacol Rev 51:63–81
Mensah-Nyagan AG, Beaujean D, Luu-The V et al (2001) Anatomical and biochemical evidence for the synthesis of unconjugated and sulfated neurosteroids in amphibians (review). Brain Res Rev 37:13–24
Murphy DD, Segal M (1996) Regulation of dendritic spine density in cultured rat hippocampal neurons by steroid hormones. J Neurosci 16:4059–4068
Orikasa C, Kondo Y, Hayashi S et al (2002) Sexually dimorphic expression of estrogen receptor beta in the anteroventral periventricular nucleus of the rat preoptic area: implication in luteinizing hormone surge. Proc Natl Acad Sci USA 99:3306–3309
Paech K, Webb P, Kuiper GG et al (1997) Differential ligand activation of estrogen receptors ERα and ERβ at AP1 sites. Science 277:1508–1510
Peluso JJ, Pappalardo A, Losel R et al (2006) Progesterone membrane receptor component 1 expression in the immature rat ovary and its role in mediating progesterone’s antiapoptotic action. Endocrinology 147:3133–3140
Pérez J, Luquín S, Naftolin F et al (1993) The role of estradiol and progesterone in phased synaptic remodeling of the rat arcuate nucleus. Brain Res 608:38–44
Price RH, Handa RJ (2000) Expression of estrogen receptor-β protein and mRNA in the cerebellum of the rat. Neurosci Lett 288:115–118
Robel P, Baulieu EE (1985) Neuro-steroids, 3β-hydroxy-Δ5-derivatives in the rodent brain. Neurochem Int 7:953–958
Robel P, Corpéchot C, Clarke C et al (1986) Neuro-steroids: 3β-hydroxy-Δ5-derivatives in the rat brain. In: Fink G, Harmar AJ, McKerns KW (eds) Neuroendocrine molecular biology. Plenum, New York
Rocamora N, Garcia-Ladona FJ, Palacios JM et al (1993) Differential expression of brain-derived neurotrophic factor, neurotrophin-3, and low-affinity nerve growth factor receptor during the postnatal development of the rat cerebellar system. Brain Res Mol Brain Res 17:1–8
Sakamoto H, Ukena K, Tsutsui K (2001a) Activity and localization of 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase in the zebrafish central nervous system. J Comp Neurol 439:291–305
Sakamoto H, Ukena K, Tsutsui K (2001b) Effects of progesterone synthesized de novo in the developing Purkinje cell on its dendritic growth and synaptogenesis. J Neurosci 21:6221–6232
Sakamoto H, Ukena K, Tsutsui K (2002) Dendritic spine formation in response to progesterone synthesized de novo in the developing Purkinje cell in rats. Neurosci Lett 322:111–115
Sakamoto H, Mezaki Y, Shikimi H et al (2003a) Dendritic growth and spine formation in response to estrogen in the developing Purkinje cell. Endocrinology 144:4466–4477
Sakamoto H, Shikimi H, Ukena K et al (2003b) Neonatal expression of progesterone receptor isoforms in the cerebellar Purkinje cell in rats. Neurosci Lett 343:163–166
Sakamoto H, Ukena K, Takemori H et al (2004) Expression and localization of 25-Dx, a membrane-associated putative progesterone-binding protein, in the developing Purkinje cell. Neuroscience 126:325–334
Sakamoto H, Ukena K, Kawata M et al (2008) Expression, localization and possible actions of 25-Dx, a membraneassociated putative progesterone-binding protein, in the developing Purkinje cell of the cerebellum: a new insight into the biosynthesis, metabolism and multiple actions of progesterone as a neurosteroid (review). Cerebellum 7:18–25
Sasahara K, Shikimi H, Haraguchi S et al (2007) Mode of action and functional significance of estrogen-inducing dendritic growth, spinogenesis, and synaptogenesis in the developing Purkinje cell. J Neurosci 27:7408–7417
Schlinger BA, Lane NI, Grisham W et al (1999) Androgen synthesis in a songbird: a study of cyp17 (17α-hydroxylase/c17,20-lyase) activity in the zebra finch. Gen Comp Endocrinol 113:46–58
Schumacher M, Weill-Engerer S, Liere P et al (2003) Steroid hormones and neurosteroids in normal and pathological aging of the nervous system. Prog Neurobiol 71:3–29
Schwartz PM, Borghesani PR, Levy RL et al (1997) Abnormal cerebellar development and foliation in BDNF−/− mice reveals a role for neurotrophins in CNS patterning. Neuron 19:269–281
Segal RA, Pomeroy SL, Stiles CD (1995) Axonal growth and fasciculation linked to differential expression of BDNF and NT3 receptors in developing cerebellar granule cells. J Neurosci 15:4970–4981
Shughrue PJ, Scrimo PJ, Merchenthaler I (2000) Estrogen binding and estrogen receptor characterization (ERα and ERβ) in the cholinergic neurons of the rat basal forebrain. Neuroscience 96:41–49
Sohrabji F, Miranda RC, Toran-Allerand CD (1995) Identification of a putative estrogen response element in the gene encoding brain-derived neurotrophic factor. Proc Natl Acad Sci USA 92:11110–11114
Soma KK, Alday NA, Hau M et al (2003) DHEA metabolism by 3β-HSD in adult zebra finch brain: sex difference and rapid effect of stress. Endocrinology 145:1668–1677
Takase M, Ukena K, Yamazaki T et al (1999) Pregnenolone, pregnenolone sulfate and cytochrome P450 side-chain cleavage enzyme in the amphibian brain and their seasonal changes. Endocrinology 140:1936–1944
Tsutsui K (2006a) Biosynthesis and organizing action of neurosteroids in the developing Purkinje cell (review). Cerebellum 5:89–96
Tsutsui K (2006b) Biosynthesis, mode of action and functional significance of neurosteroids in the developing Purkinje cell (review). J Steroid Biochem Mol Biol 102:187–194
Tsutsui K (2008a) Progesterone biosynthesis and action in the developing neuron (review). Endocrinology 149:2757–2761
Tsutsui K (2008b) Neurosteroids in the Purkinje cell: biosynthesis, mode of action and functional significance (review). Mol Neurobiol 37:116–125
Tsutsui K, Mellon SH (2006) Neurosteroids in the brain neuron: biosynthesis, action and medicinal impact on neurodegenerative disease (review). Cent Nerv Syst Agents Med Chem 6:73–82
Tsutsui K, Schlinger BA (2001) Steroidogenesis in the avian brain. In: Dawson A, Chaturvedi CM (eds) Avian endocrinology. Narosa Publishing House, New Delhi
Tsutsui K, Ukena K (1999) Neurosteroids in the cerebellar Purkinje neuron and their actions (review). Int J Mol Med 4:49–56
Tsutsui K, Yamazaki T (1995) Avian neurosteroids. I. Pregnenolone biosynthesis in the quail brain. Brain Res 678:1–9
Tsutsui K, Usui M, Yamazaki T et al (1997a) Neurosteroids in the avian brain. In: Maitra SK (ed) Frontiers in environmental and metabolic endocrinology. Burdwan Press, Burdwan
Tsutsui K, Yamazaki T, Usui M et al (1997b) P450scc activity in the brain. In: Harvey S, Etches RJ (eds) Perspectives in avian endocrinology. J Endocrinol, Bristol
Tsutsui K, Ukena K, Takase M et al (1999) Neurosteroid biosynthesis in vertebrate brains (review). Comp Biochem Physiol C 124:121–129
Tsutsui K, Ukena K, Usui M et al (2000) Novel brain function: biosynthesis and actions of neurosteroids in neurons (review). Neurosci Res 36:261–273
Tsutsui K, Matsunaga M, Ukena K (2003a) Biosynthesis and biological actions of neurosteroids in the avian brain (review). Avian Poultry Biol Rev 14:63–78
Tsutsui K, Sakamoto H, Ukena K (2003b) Biosynthesis and action of neurosteroids in the cerebellar Purkinje neuron. J Steroid Biochem Mol Biol 85:311–321
Tsutsui K, Ukena K, Sakamoto H (2003c) A novel aspect of the cerebellum: biosynthesis of neurosteroids in the Purkinje cell (review). Cerebellum 2:215–222
Tsutsui K, Sakamoto H, Shikimi H et al (2004) Organizing actions of neurosteroids in the Purkinje neuron (review). Neurosci Res 49:273–279
Tsutsui K, Matsunaga M, Miyabara et al (2006) Neurosteroid biosynthesis in the quail brain (review). J Exp Zool 305A:733–742
Ukena K, Usui M, Kohchi C et al (1998) Cytochrome P450 side-chain cleavage enzyme in the cerebellar Purkinje neuron and its neonatal change in rats. Endocrinology 139:137–147
Ukena K, Honda Y, Inai Y et al (1999a) Expression and activity of 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase in different regions of the avian brain. Brain Res 818:536–542
Ukena K, Kohchi C, Tsutsui K (1999b) Expression and activity of 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase in the rat Purkinje neuron during neonatal life. Endocrinology 140:805–813
Ukena K, Honda Y, Lea RW et al (2001) Developmental changes in progesterone biosynthesis and metabolism in the quail brain. Brain Res 898:190–194
Usui M, Yamazaki T, Kominami S et al (1995) Avian neurosteroids. II. Localization of a cytochrome P450scc-like substance in the quail brain. Brain Res 678:10–20
Vanson A, Arnold AP, Schlinger BA (1996) 3β-Hydroxysteroid dehydrogenase/isomerase and aromatase activity in primary cultures of developing zebra finch telencephalon: dehydroepiandrosterone as substrate for synthesis of androstenedione and estrogens. Gen Comp Endocrinol 102:342–350
Wang T, Xie K, Lu B (1995) Neurotrophins promote maturation of developing neuromuscular synapses. J Neurosci 15:4796–4805
Webb P, Lopez GN, Uht RM et al (1995) Tamoxifen activation of the estrogen receptor/AP-1 pathway: potential origin for the cell-specific estrogen-like effects of antiestrogens. Mol Endocrinol 9:443–456
Woolley CS, McEwen BS (1994) Estradiol regulates hippocampal dendritic spine density via an N-methyl-D-aspartate receptor-dependent mechanism. J Neurosci 14:7680–7687
Woolley CS, Gould E, Frankfurt M et al (1990) Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons. J Neurosci 10:4035–4039
Acknowledgments
The author thanks Hirotaka Sakamoto, Kazuyoshi Ukena, Mariko Usui, Hanako Shikimi, Katsunori Sasahara, Shogo Haraguchi, Asami Sekine, Shin-ichiro Okuyama, Shin-ichiro Honda, Nobuhiro Harada, and Mitsuhiro Kawata for their work cited in this manuscript.
Grant support: Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan (18107002, 22132004 and 22227002 to K. T.).
Disclosure Statement: The author has nothing to disclose.
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Tsutsui, K. (2013). Neurosteroids and Synaptic Formation in the Cerebellum. In: Manto, M., Schmahmann, J.D., Rossi, F., Gruol, D.L., Koibuchi, N. (eds) Handbook of the Cerebellum and Cerebellar Disorders. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-1333-8_42
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