Abstract
Neuroactive steroids regulate neuronal and glial function via non-genomic mechanisms by interacting with ion channels and neurotransmitter receptors. The adrenal glands and gonads are important sources of neuroactive steroids. In addition, neuroactive steroids can be produced locally within the central nervous system and these agents are denoted as neurosteroids. Enzymes involved in neurosteroid biosynthesis are expressed in the cerebellum, where these agents modulate the development of cerebellar neurons as well as glial cells. Neurosteroids also exert neuroprotective actions and modulate synaptic transmission and plasticity in mature neurons. Deficits in cerebellar neuroactive steroid signaling may play a role in the pathophysiology of several conditions involving the cerebellum, including Niemann–Pick type C disease, gestational dietary deficiency of methyl donors (folate and vitamin B12), prenatal stress, brain tumors, schizophrenia, autism, mood disorders, and alcohol use disorder. In addition, neuroactive steroids are emerging as potential therapeutic agents for a number of diseases that impair cerebellar function.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
AgĂs-Balboa RC, Pinna G, Zhubi A et al (2006) Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis. Proc Natl Acad Sci U S A 103:14602–14607
Andreescu CE, Milojkovic BA, Haasdijk ED et al (2007) Estradiol improves cerebellar memory formation by activating estrogen receptor beta. J Neurosci 27:10832–10839
Ardeshiri A, Kelley MH, Korner IP, Hurn PD, Herson PS (2006) Mechanism of progesterone neuroprotection of rat cerebellar Purkinje cells following oxygen-glucose deprivation. Eur J Neurosci 24:2567–2574
Belcher SM (2008) Rapid signaling mechanisms of estrogens in the develo** cerebellum. Brain Res Rev 57:481–492
Belcher SM, Ma X, Le HH (2009) Blockade of estrogen receptor signaling inhibits growth and migration of medulloblastoma. Endocrinology 150:1112–1121
Belcher SM, Burton CC, Cookman CJ et al (2017) Estrogen and soy isoflavonoids decrease sensitivity of medulloblastoma and central nervous system primitive neuroectodermal tumor cells to chemotherapeutic cytotoxicity. BMC Pharmacol Toxicol 18:63
Bennett GA, Palliser HK, Shaw JC, Palazzi KL, Walker DW, Hirst JJ (2017) Maternal stress in pregnancy affects myelination and neurosteroid regulatory pathways in the Guinea pig cerebellum. Stress 20:580–588
Biamonte F, Assenza G, Marino R et al (2009) Interactions between neuroactive steroids and reelin haploinsufficiency in Purkinje cell survival. Neurobiol Dis 36:103–115
Caldeira JC, Wu Y, Mameli M et al (2004) Fetal alcohol exposure alters neurosteroid levels in the develo** rat brain. J Neurochem 90:1530–1539
Caruso D, Pesaresi M, Abbiati F et al (2013) Comparison of plasma and cerebrospinal fluid levels of neuroactive steroids with their brain, spinal cord and peripheral nerve levels in male and female rats. Psychoneuroendocrinology 38:2278–2290
Caruso D, Melis M, Fenu G et al (2014) Neuroactive steroid levels in plasma and cerebrospinal fluid of male multiple sclerosis patients. J Neurochem 130:591–597
Cookman CJ, Belcher SM (2015) Estrogen receptor-β up-regulates IGF1R expression and activity to inhibit apoptosis and increase growth of medulloblastoma. Endocrinology 156:2395–2408
Cooper EJ, Johnston GA, Edwards FA (1999) Effects of a naturally occurring neurosteroid on GABAA IPSCs during development in rat hippocampal or cerebellar slices. J Physiol 521(Pt 2):437–449
Dean SL, McCarthy MM (2008) Steroids, sex and the cerebellar cortex: implications for human disease. Cerebellum 7:38–47
Dean SL, Wright CL, Hoffman JF, Wang M, Alger BE, McCarthy MM (2012) Prostaglandin E2 stimulates estradiol synthesis in the cerebellum postnatally with associated effects on Purkinje neuron dendritic arbor and electrophysiological properties. Endocrinology 153:5415–5427
Dieni CV, Ferraresi A, Sullivan JA, Grassi S, Pettorossi VE, Panichi R (2018a) Acute inhibition of estradiol synthesis impacts vestibulo-ocular reflex adaptation and cerebellar long-term potentiation in male rats. Brain Struct Funct 223:837–850
Dieni CV, Sullivan JA, Faralli M et al (2018b) 17 beta-estradiol synthesis modulates cerebellar dependent motor memory formation in adult male rats. Neurobiol Learn Mem 155:276–286
Dieni CV, Contemori S, Biscarini A, Panichi R (2020) De novo synthesized estradiol: a role in modulating the cerebellar function. Int J Mol Sci 21:3316
Diviccaro S, Caputi V, Cioffi L et al (2021) Exploring the impact of the microbiome on neuroactive steroid levels in germ-free animals. Int J Mol Sci 22:12551
El Hajj Chehadeh S, Dreumont N, Willekens J et al (2014) Early methyl donor deficiency alters cAMP signaling pathway and neurosteroidogenesis in the cerebellum of female rat pups. Am J Physiol Endocrinol Metab 307:E1009–E1019
Fanelli F, Marino R, Keller F (2013) Focusing on the interactions between the GABAergic system and neurosteroids in neurodevelopmental disorders. Curr Pharm Des 19:6491–6498
Gatta E, Guidotti A, Saudagar V et al (2021) Epigenetic regulation of GABAergic neurotransmission and neurosteroid biosynthesis in alcohol use disorder. Int J Neuropsychopharmacol 24:130–141
Ghoumari AM, Ibanez C, El-Etr M et al (2003) Progesterone and its metabolites increase myelin basic protein expression in organotypic slice cultures of rat cerebellum. J Neurochem 86:848–859
Griffin LD, Gong W, Verot L, Mellon SH (2004) Niemann-pick type C disease involves disrupted neurosteroidogenesis and responds to allopregnanolone. Nat Med 10:704–711
Guennoun R (2020) Progesterone in the brain: hormone, neurosteroid and neuroprotectant. Int J Mol Sci 21:5271
Hamann M, Rossi DJ, Attwell D (2002) Tonic and spillover inhibition of granule cells control information flow through cerebellar cortex. Neuron 33:625–633
Haraguchi S, Hara S, Ubuka T, Mita M, Tsutsui K (2012) Possible role of pineal allopregnanolone in Purkinje cell survival. Proc Natl Acad Sci U S A 109:21110–21115
Hedges VL, Ebner TJ, Meisel RL, Mermelstein PG (2012) The cerebellum as a target for estrogen action. Front Neuroendocrinol 33:403–411
Hirtz A, Rech F, Dubois-Pot-Schneider H, Dumond H (2020) Astrocytoma: a hormone-sensitive tumor? Int J Mol Sci 21:9114
Janmaat S, Akwa Y, Doulazmi M et al (2011) Age-related Purkinje cell death is steroid dependent: RORα haplo-insufficiency impairs plasma and cerebellar steroids and Purkinje cell survival. Age (Dordr) 33:565–578
Jung ME, Yang SH, Brun-Zinkernagel AM, Simpkins JW (2002) Estradiol protects against cerebellar damage and motor deficit in ethanol-withdrawn rats. Alcohol 26:83–93
Kelley MH, Kuroiwa M, Taguchi N, Herson PS (2011) Sex difference in sensitivity to allopregnanolone neuroprotection in mice correlates with effect on spontaneous inhibitory post synaptic currents. Neuropharmacology 61:724–729
Kiyokage E, Toida K, Suzuki-Yamamoto T, Ishimura K (2014) Cellular localization of 5α-reductase in the rat cerebellum. J Chem Neuroanat 59-60:8–16
KrĂz L, BicĂková M, Mohapl M, Hill M, CernĂ˝ I, Hampl R (2008) Steroid sulfatase and sulfuryl transferase activities in human brain tumors. J Steroid Biochem Mol Biol 109:31–39
Kudova E (2021) Rapid effects of neurosteroids on neuronal plasticity and their physiological and pathological implications. Neurosci Lett 750:135771
Langmade SJ, Gale SE, Frolov A et al (2006) Pregnane X receptor (PXR) activation: a mechanism for neuroprotection in a mouse model of Niemann-pick C disease. Proc Natl Acad Sci U S A 103:13807–13812
Lloyd-Evans E, Waller-Evans H (2020) Biosynthesis and signalling functions of central and peripheral nervous system neurosteroids in health and disease. Essays Biochem 64:591–606
Mahfouz A, Lelieveldt BP, Grefhorst A et al (2016) Genome-wide coexpression of steroid receptors in the mouse brain: identifying signaling pathways and functionally coordinated regions. Proc Natl Acad Sci U S A 113:2738–2743
Manca P, Mameli O, Caria MA, Torrejón-Escribano B, Blasi J (2014) Distribution of SNAP25, VAMP1 and VAMP2 in mature and develo** deep cerebellar nuclei after estrogen administration. Neuroscience 266:102–115
Mirzatoni A, Spence RD, Naranjo KC, Saldanha CJ, Schlinger BA (2010) Injury-induced regulation of steroidogenic gene expression in the cerebellum. J Neurotrauma 27:1875–1882
Morrison JL, Botting KJ, Darby JRT et al (2018) Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic. J Physiol 596:5535–5569
Moulton EA, Elman I, Becerra LR, Goldstein RZ, Borsook D (2014) The cerebellum and addiction: insights gained from neuroimaging research. Addict Biol 19:317–331
Murugan S, Jakka P, Namani S, Mujumdar V, Radhakrishnan G (2019) The neurosteroid pregnenolone promotes degradation of key proteins in the innate immune signaling to suppress inflammation. J Biol Chem 294:4596–4607
Pillerová M, Borbélyová V, Hodosy J et al (2021) On the role of sex steroids in biological functions by classical and non-classical pathways. An update. Front Neuroendocrinol 62:100926
Potts MB, Adwanikar H, Noble-Haeusslein LJ (2009) Models of traumatic cerebellar injury. Cerebellum 8:211–221
Sakamoto H, Mezaki Y, Shikimi H, Ukena K, Tsutsui K (2003) Dendritic growth and spine formation in response to estrogen in the develo** Purkinje cell. Endocrinology 144:4466–4477
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 develo** Purkinje cell. J Neurosci 27:7408–7417
Schverer M, Lanfumey L, Baulieu EE, Froger N, Villey I (2018) Neurosteroids: non-genomic pathways in neuroplasticity and involvement in neurological diseases. Pharmacol Ther 191:190–206
Smith SS (1989) Estrogen administration increases neuronal responses to excitatory amino acids as a long-term effect. Brain Res 503:354–357
Tozzi A, Bellingacci L, Pettorossi VE (2020) Rapid estrogenic and androgenic neurosteroids effects in the induction of long-term synaptic changes: implication for early memory formation. Front Neurosci 14:572511
Tsutsui K, Haraguchi S (2020) Neuroprotective actions of cerebellar and pineal allopregnanolone on Purkinje cells. FASEB Bioadv 2:149–159
Tsutsui K, Ukena K, Sakamoto H, Okuyama S, Haraguchi S (2011) Biosynthesis, mode of action, and functional significance of neurosteroids in the purkinje cell. Front Endocrinol (Lausanne) 2:61
Ukena K, Usui M, Kohchi C, Tsutsui K (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, Kohchi C, Lea RW, Tsutsui K (1999) Expression and activity of 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4-isomerase in different regions of the avian brain. Brain Res 818:536–542
Valenzuela CF, Partridge LD, Mameli M, Meyer DA (2008) Modulation of glutamatergic transmission by sulfated steroids: role in fetal alcohol spectrum disorder. Brain Res Rev 57:506–519
Vicini S, Losi G, Homanics GE (2002) GABA(A) receptor delta subunit deletion prevents neurosteroid modulation of inhibitory synaptic currents in cerebellar neurons. Neuropharmacology 43:646–650
Xu J, Zhou Y, Yan C et al (2022) Neurosteroids: a novel promise for the treatment of stroke and post-stroke complications. J Neurochem 160:113–127
Yan M, Liu AL, Zhou SJ et al (2015) Characterization of a synthetic steroid 24-keto-cholest-5-en-3β, 19-diol as a neuroprotectant. CNS Neurosci Ther 21:486–495
Yarim M, Kabakci N (2004) Neurosteroidogenesis in oligodendrocytes and Purkinje neurones of cerebellar cortex of dogs. Anat Histol Embryol 33:151–154
Yawno T, Hirst JJ, Castillo-Melendez M, Walker DW (2009) Role of neurosteroids in regulating cell death and proliferation in the late gestation fetal brain. Neuroscience 163:838–847
Zamudio-Bulcock PA, Valenzuela CF (2011) Pregnenolone sulfate increases glutamate release at neonatal climbing fiber-to-Purkinje cell synapses. Neuroscience 175:24–36
Zamudio-Bulcock PA, Everett J, Harteneck C, Valenzuela CF (2011) Activation of steroid-sensitive TRPM3 channels potentiates glutamatergic transmission at cerebellar Purkinje neurons from develo** rats. J Neurochem 119:474–485
Zsarnovszky A, Kiss D, Jocsak G, Nemeth G, Toth I, Horvath TL (2018) Thyroid hormone- and estrogen receptor interactions with natural ligands and endocrine disruptors in the cerebellum. Front Neuroendocrinol 48:23–36
Acknowledgements
We dedicate this book chapter to the late Professor Kazuyoshi Tsutsui (1952–2021) from the Department of Biology at Waseda University in Japan for his groundbreaking work on cerebellar neurosteroids. Dr. Valenzuela’s lab is supported by the National Institute of Health grants R01 AA015614 and P50 AA022534.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this chapter
Cite this chapter
Valenzuela, C.F., Varela, S. (2023). Neuroactive Steroids. In: Gruol, D.L., Koibuchi, N., Manto, M., Molinari, M., Schmahmann, J.D., Shen, Y. (eds) Essentials of Cerebellum and Cerebellar Disorders. Springer, Cham. https://doi.org/10.1007/978-3-031-15070-8_37
Download citation
DOI: https://doi.org/10.1007/978-3-031-15070-8_37
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-15069-2
Online ISBN: 978-3-031-15070-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)