ReviewThe cerebellum as a target for estrogen action
Highlights
► Estrogen action in the cerebellum has been observed for years, but often ignored. ► Estradiol affects cerebellar development. ► Estradiol promotes glutamate neurotransmission within the cerebellum. ► Cerebellar estradiol is impacts a variety of health issues.
Introduction
Studies characterizing the effects of steroid hormones on neural function have often taken a logical and programmatic approach. By first utilizing methods to identify brain nuclei which contain steroid hormone receptors, researchers would then examine the cellular mechanisms of steroid action on those nerve cells. The work would culminate in an understanding of the physiological and behavioral functions nested within the neural circuitry encompassing the steroid responsive neurons (Pfaff, 1980). For estradiol, the classic autoradiographic studies (e.g., Pfaff and Keiner, 1973) highlighted the basal forebrain, including the hypothalamus, as the primary region in which cellular uptake of radioactive estradiol occurred. Many studies followed, demonstrating the importance of estradiol on a variety of behaviors related to reproduction (Davis et al., 1979, Floody and Pfaff, 1977, Kow and Pfaff, 1975, Pfaff and Keiner, 1973, Pfaff, 1980).
As valuable as the initial autoradiography technique was to identify brain regions sensitive to estradiol, it became clear that this method is useful primarily in identifying areas in which estrogen receptor expression is abundant. The natural tendency by investigators, often stated explicitly, was to suggest that brain regions exhibiting lower radioactive signals were less, or not at all influenced by the hormone (Amateau et al., 2004, Rogers et al., 1993, Torres-Aleman et al., 1992, Westley and Salaman, 1977). In a simple system, in which estradiol had just one receptor and one mechanism of action, such an assumption could be easily justified. We now know, however, that there are multiple estrogen receptors, each of which can affect numerous cellular signaling pathways (McDevitt et al., 2008, Mermelstein, 2009, Mermelstein and Micevych, 2008, Micevych et al., 2009, Raz et al., 2008). Many of these actions require only a few receptors to produce pronounced changes in cellular function. Thus, the conclusions drawn from these foundational autoradiography discoveries have led to many false negatives regarding neuronal tissue sensitive to hormonal manipulation.
One such brain area considered insensitive to estradiol has been the cerebellum. This structure, with unique cell types and cytoarchitecture (Eccles et al., 1967, Ito, 2006, Palay and Chan-Palay, 1974), regulates a variety of behaviors including motor control, language, attention, and memory (Bloedel and Bracha, 1997, Strick et al., 2009). Over many years, several key findings have emerged that redefine the cerebellum as a target of estradiol action. More sensitive detection methods have determined a much wider distribution of estrogen-responsive brain regions, including the cerebellum. Another critical observation has been that estrogens guide cerebellar development. Additionally, the cerebellum itself may be a source of estradiol, through local steroid hormone synthesis. Estradiol also appears to directly affect cerebellar glutamatergic neurotransmission, provides protection against toxic insults, and impacts a variety of health related cerebellar functions. Yet, remarkably, the canon that the cerebellum is unresponsive to estradiol remains. This review examines each of these topics in turn. In addition, we will offer new in vivo data demonstrating that estradiol modulates glutamate neurotransmission in the cerebellum through locally synthesized estradiol. We conclude that the coalescence of data in support of estradiol regulation of cerebellar functioning is persuasive. That said, our understanding of the roles of estrogen signaling in the cerebellum is still in its infancy.
Section snippets
Estrogen receptors and estradiol synthesis in the cerebellum
Before the first cloning of estrogen receptor α (ERα), estrogen responsive neurons were detected by examining for radiolabeled estradiol accumulation. As mentioned in the Introduction, this led to the identification and characterization of hypothalamic and other diencephalic structures involved in reproduction. Interestingly, estradiol uptake was also observed in the cerebellum, albeit to a far lesser extent (McEwen and Pfaff, 1970, McEwen et al., 1970a, McEwen et al., 1970b). This surprising
Estrogens and cerebellar development
The development of the cerebellum has been detailed in several excellent reviews (Altman and Bayer, 1997, Carletti and Rossi, 2008, Millen and Gleeson, 2008, Sillitoe and Joyner, 2007). In regard to the actions of estrogens, a different pattern of estradiol binding is observed during development compared to the adult, beginning in the late postnatal period (Vito and Fox, 1979) and continuing up until weaning (MacLusky et al., 1979b). Ikeda and Nagai (2006) demonstrated that ERα mRNA is
Estrogen facilitation of cerebellar glutamatergic signaling
While it has become clear that estradiol affects cerebellar function, the mechanisms of action are not well understood. Sheryl Smith and colleagues pioneered the concept that of estrogens augment glutamatergic neurotransmission in the adult. In their initial studies, estrogens applied either directly to the cerebellum or i.v. in anesthetized adult (ovariectomized) rats resulted in an increase in Purkinje cell responsiveness to microionotophoresis-applied glutamate. The local effects of
Health implications
An important extension of the observations that estradiol affects cerebellar development and promotes neuronal excitatory neurotransmission in the adult, is the functional significance for human health. While these types of studies typically use systemic estrogen treatment, and thus the observed effects cannot be definitively attributed to the hormone acting directly and solely upon this brain region, the impact of estrogen treatment on cerebellar functioning is unequivocal.
Estradiol action has
Conclusions and future directions
Once thought to be extraneous regarding estradiol action, the cerebellum is now known to be a brain structure affected by this hormone, leading to alterations in a variety of behaviors. Although not described in detail here, there is also growing evidence that the cerebellum contributes to sex differences in the pathology of autism, attention-deficit hyperactivity disorder, schizophrenia, and depression (for a review see Dean and McCarthy, 2008). Whether this is due to sex differences in
Acknowledgments
This work was supported by DA013680, Core funding NS062158, NS048944, NS077661 and NSF IOS-1146016.
References (177)
- et al.
Cerebellar degeneration associated with chronic alcoholism
J. Neurol. Sci.
(1966) - et al.
Estradiol synthesis within the human brain
Neuroscience
(2011) - et al.
Is brain estradiol a hormone or a neurotransmitter?
Trends Neurosci.
(2006) - et al.
Rapid changes in production and behavioral action of estrogens
Neuroscience
(2006) - et al.
The influence of estrous cycle and intrastriatal estradiol on sensorimotor performance in the female rat
Pharmacol. Biochem. Behav.
(1987) Regulated expression of estrogen receptor alpha and beta mRNA in granule cells during development of the rat cerebellum
Brain Res. Dev. Brain Res.
(1999)- et al.
Duality of cerebellar motor and cognitive functions
Int. Rev. Neurobiol.
(1997) - et al.
Brain neurotoxicity of Penitrem A: electrophysiological, behavioral and histopathological study
Toxicon
(1998) - et al.
Stimulatory effect of beta-estradiol treatment on GABA-degradative enzymes within rat cerebellar cortex
Neurosci. Lett.
(1983) - et al.
Estrogen-mediated neuroprotection in the cortex may require NMDA receptor activation
Neuroscience
(2007)
Role of astrocytes in estrogen-mediated neuroprotection
Exp. Gerontol.
Chronic ethanol consumption: from neuroadaptation to neurodegeneration
Prog. Neurobiol.
Dehydroepiandrosterone sulfate improves memory in aging mice
Brain Res.
Dehydroepiandrosterone and its sulfate enhance memory retention in mice
Brain Res.
Glia–neuron crosstalk in the neuroprotective mechanisms of sex steroid hormones
Brain Res. Brain Res. Rev.
Effects of estrogens on cognition and brain morphology: involvement of the cerebellum
Maturitas
Hormones and regional brain blood flow
Pharmacol. Biochem. Behav.
Transcriptional activity of estrogen receptors ERalpha and ERbeta in the EtC.1 cerebellar granule cell line
Brain Res.
Classification of the hereditary ataxias and paraplegias
Lancet
Tonic synaptic inhibition modulates neuronal output pattern and spatiotemporal synaptic integration
Neuron
Menopause and mitochondria: windows into estrogen effects on Alzheimer’s disease risk and therapy
Prog. Brain Res.
Estrogen regulation of GABA transmission in rat preoptic area
Brain Res. Bull.
Regional changes in amino acid concentration in the developing brain and the effects of neonatal administration of estradiol
Brain Res.
Differential expression of the estrogen receptors alpha and beta during postnatal development of the rat cerebellum
Brain Res.
Cerebellar circuitry as a neuronal machine
Prog. Neurobiol.
Estradiol protects against cerebellar damage and motor deficit in ethanol-withdrawn rats
Alcohol
Acute effect of intranasal estrogen on cerebral and cerebellar perfusion in postmenopausal women
Maturitas
Rapid actions of plasma membrane estrogen receptors
Trends Endocrinol. Metab.
Induction of lordosis in female rats: two modes of estrogen action and the effect of adrenalectomy
Horm. Behav.
Protective effects of 17beta estradiol on altered age related neuronal parameters in female rat brain
Neurosci. Lett.
Estradiol rescues neurons from global ischemia-induced cell death: multiple cellular pathways of neuroprotection
Steroids
The development of estrogen receptor systems in the rat brain and pituitary: postnatal development
Brain Res.
The development of estrogen receptor systems in the rat brain: perinatal development
Brain Res.
The interactive effects of alcohol and temazepam on P300 and reaction time
Brain Cogn.
Sigma1 (sigma 1) receptor agonists and neurosteroids attenuate B25–35-amyloid peptide-induced amnesia in mice through a common mechanism
Neuroscience
New insights into the classical and non-classical actions of estrogen: evidence from estrogen receptor knock-out and knock-in mice
Mol. Cell. Endocrinol.
Factors influencing sex hormone uptake by rat brain regions. I. Effects of neonatal treatment, hypophysectomy, and competing steroid on estradiol uptake
Brain Res.
Estradiol and progesterone regulate neuronal structure and synaptic connectivity in adult as well as developing brain
Exp. Gerontol.
Factors influencing sex hormone uptake by rat brain regions. 3. Effects of competing steroids on testosterone uptake
Brain Res.
Factors influencing sex hormone uptake by rat brain regions. II. Effects of neonatal treatment and hypophysectomy on testosterone uptake
Brain Res.
Cerebellar development and disease
Curr. Opin. Neurobiol.
Molecular genetics and pathogenesis of Friedreich ataxia
Neuromuscul. Disord.
Development of the Cerebellar System in Relation to Its Evolution, Structures and Functions
Brain estradiol content in newborn rats: sex differences, regional heterogeneity, and possible de novo synthesis by the female telencephalon
Endocrinology
Estradiol improves cerebellar memory formation by activating estrogen receptor beta
J. Neurosci.
The relationship of intrinsic fall risk factors to a recent history of falling in older women with osteoporosis
J. Orthop. Sports Phys. Ther.
Pathogenesis in menstrual cycle-linked CNS disorders
Ann. N. Y. Acad. Sci.
Abnormalities in the climbing fiber-Purkinje cell circuitry contribute to neuronal dysfunction in ATXN1 [82Q] mice
J. Neurosci.
Predictors of falls among postmenopausal women: results from the National Osteoporosis Risk Assessment (NORA)
Osteoporos. Int.
Association between hormone replacement therapy and subsequent stroke: a meta-analysis
BMJ
Cited by (67)
Better with age: Developmental changes in oscillatory activity during verbal working memory encoding and maintenance
2024, Developmental Cognitive NeuroscienceThe CODECS study: COgnitive DEficits in Cerebellar Stroke
2023, Brain and CognitionThe association of reproductive stage with lobular cerebellar network connectivity across female adulthood
2022, Neurobiology of AgingDevelopmental expression of genes involved in progesterone synthesis, metabolism and action during the post-natal cerebellar myelination
2021, Journal of Steroid Biochemistry and Molecular BiologyCitation Excerpt :In this regard, it has been proposed that the disrupted supply of progesterone and estradiol after early preterm birth may contribute to the frequently observed impairment of neurodevelopment, with delayed psychomotor and mental progress and sometimes severe neurological deficits like cerebral palsy [64,65]. Interestingly, increasing evidence indicate that even low estrogen concentration can modulate synaptic activity by a rapid and dynamic regulation of its synthesis and availability at the site of action [62,63]. The significant and stable levels of cerebellar estradiol (20–50 pg/g) measured from P5 to P35 may reflect its essential role in the neonatal period.