Estrogen receptors in the central nervous system and their implication for dopamine-dependent cognition in females

Abstract

Over the past 30 years, research has demonstrated that estrogens are not only important for female reproduction, but play a role in a diverse array of cognitive functions. Originally, estrogens were thought to have only one receptor, localized exclusively to the cytoplasm and nucleus of cells. However, it is now known that there are at least three estrogen receptors (ERs): ERα, ERβ and G-protein coupled ER1 (GPER1). In addition to being localized to nuclei, ERα and ERβ are localized to the cell membrane, and GPER1 is also observed at the cell membrane. The mechanism through which ERs are associated with the membrane remains unclear, but palmitoylation of receptors and associations between ERs and caveolin are implicated in membrane association. ERα and ERβ are mostly observed in the nucleus using light microscopy unless they are particularly abundant. However, electron microscopy has revealed that ERs are also found at the membrane in complimentary distributions in multiple brain regions, many of which are innervated by dopamine inputs and were previously thought to contain few ERs. In particular, membrane-associated ERs are observed in the prefrontal cortex, dorsal striatum, nucleus accumbens, and hippocampus, all of which are involved in learning and memory. These findings provide a mechanism for the rapid effects of estrogens in these regions. The effects of estrogens on dopamine-dependent cognition likely result from binding at both nuclear and membrane-associated ERs, so elucidating the localization of membrane-associated ERs helps provide a more complete understanding of the cognitive effects of these hormones.

Reproductive steroid receptors and actions in the locus coeruleus of male macaques: Part of an aggression circuit?

“…GPER1, the membrane E-receptor, has been found throughout the rodent brain with high levels in the olfactory bulbs, hypothalamus, LC, the hippocampus, the habenular nucleus of the epithalamus, nucleus of the solitary tract, cortical regions including the motor, somatosensory piriform cortices, as well as the Purkinje and granule cells of the cerebellum (Almey et al, 2015). While many functions of GPER1 have been described, information on the hormonal regulation of GPER1 is limited.…”

“…Moreover, these rapid actions may initiate and support longer term actions on gene expression (Levin, 2015). For example, the estrogen specific membrane protein, GPER1, is ubiquitously expressed and found in many areas of the brain (Almey et al, 2015). …”

Emerging roles for the novel estrogen-sensing receptor GPER1 in the CNS

“…Several studies have examined the localisation of GPER1 in rodent brain and have reported high levels of GPER1 expression in both cortical and hippocampal regions (Brailoiu et al, 2007;Hazell et al, 2009;Almey et al, 2014;Almey et al, 2015). Expression of GPER1 has also been detected in the basal forebrain, thalamus and dorsal striatum (Brailoiu et al, 2007;Hazell et al, 2009).…”

Tamoxifen and amphetamine abuse: Are there therapeutic possibilities?

“…The effect on dopamine systems could underlie some of the sex differences in motivated behavior (Yoest et al, 2014). Estrogen receptor subtypes α and β as well as GPER1 are located in both nuclei and membranes in dopaminergic areas (Almey et al, 2015). While concentrations of ERα are low in dopamine neurons, ERβ is relatively abundant in dopamine cell bodies in the substantia and ventral tegmental area in both male and female rats (Creutz and Kritzer, 2002).…”