Review
The cerebellum as a target for estrogen action

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Abstract

This review focuses on the effects of estrogens upon the cerebellum, a brain region long ignored as a site of estrogen action. Highlighted are the diverse effects of estradiol within the cerebellum, emphasizing the importance of estradiol signaling in cerebellar development, modulation of synaptic neurotransmission in the adult, and the potential influence of estrogens on various health and disease states. We also provide new data, consistent with previous studies, in which locally synthesized estradiol modulates cerebellar glutamatergic neurotransmission, providing one underlying mechanism by which the actions of estradiol can affect this brain region.

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.

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