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Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York 10021
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ABSTRACT |
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 TOP ABSTRACT I. IntroductionII. Intracellular Mechanisms of Estrogen...III. Estrogen Actions Throughout the...IV. Estrogen Actions on Midbrain Raphe...V. Estrogen Actions in Hippocampus re:...V. Possible Functional SignificanceVI. ConclusionsREFERENCES |
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). It is also likely that estrogens may locally regulate events at the sites of synaptic contact in the excitatory pyramidal neurons where the synapses form. Indeed, recent ultrastructural data reveal extranuclear ER immunoreactivity within select dendritic spines on hippocampal principal cells, axons, axon terminals, and glial processes. In particular, the presence of ER in dendrites is consistent with a model for synapse formation in which filopodia from dendrites grow out to find new synaptic contacts and estrogens regulate local, post-transcriptional events via second messenger systems. |
I. Introduction |
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TOPABSTRACTI. IntroductionII. Intracellular Mechanisms of Estrogen...III. Estrogen Actions Throughout the...IV. Estrogen Actions on Midbrain Raphe...V. Estrogen Actions in Hippocampus re:...V. Possible Functional SignificanceVI. ConclusionsREFERENCES |
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Although most of the animal studies cited above focused on estrogen actions on the hypothalamus affecting ovulation and reproductive behavior, it is now apparent in animal models and clinical studies that estrogens exert many actions outside of reproductive function, including actions on brain areas that are important for learning and memory and for emotions and affective state as well as motor coordination and pain sensitivity. These effects reflect the actions of estrogens on a large number of brain areas outside of the hypothalamus, such as the midbrain and brain stem neurons that produce serotonin and catecholamines, spinal cord, cerebral cortex, and hippocampus. The problem in these brain regions has been to recognize the receptors and mechanisms by which estrogens produce their effects.
This review will focus on two aspects. First, the cellular and molecular mechanisms by which estrogens produce their diverse effects on the brain. Second, the brain regions and cell types in which estrogens produce their effects, emphasizing new knowledge regarding estrogen actions outside of the hypothalamus and pituitary gland. The serotonin system will be discussed as an example as well as the hippocampus. We will discuss the actions of estrogens in regulating synapse formation in hippocampus because they reflect a novel, nonreproductive action of estrogens related to cognitive function that is relevant for postmenopausal changes. Furthermore, these actions also illustrate the emerging evidence that estrogens act via mechanisms other than the classical cell nuclear estrogen receptors (ERs).
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II. Intracellular Mechanisms of Estrogen Action in the Central Nervous System |
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TOPABSTRACTI. IntroductionII. Intracellular Mechanisms of Estrogen...III. Estrogen Actions Throughout the...IV. Estrogen Actions on Midbrain Raphe...V. Estrogen Actions in Hippocampus re:...V. Possible Functional SignificanceVI. ConclusionsREFERENCES |
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and ERß (see McEwen and Alves, 1999, for summary).
Measurements of mRNA for ER and ERß reveal distributions in the body that differ quite markedly from each other, with moderate to high expression of ER in pituitary, kidney, epididymus, and adrenal; moderate to high expression of ERß in prostate, lung, bladder, and brain; and overlapping high expression in ovary, testis, and uterus (Kuiper et al., 1998). Isoforms of ERß are now being identified (see McEwen and Alves, 1999, for summary). The best characterized of these splice variants is ERß2, as opposed to the originally identified isoform, ERß1. ERß2 appears to have a lower affinity for estrogens than ERß1, presumably due to an 18 amino acid insertion in the ligand-binding domain (Maruyama et al., 1998). There are other splice variants of ERß with differential expression in brain and other tissues, including a variant missing Exon 4 that does not bind estradiol in hippocampus (Price et al., 2000).
In brain, the distribution of ER is fairly well established but there is less certainty surrounding the localization of ERß. Autoradiographic maps of 3H estradiol uptake and retention in brain (Stumpf and Sar, 1976; Pfaff, 1980) are presumed to reflect binding to all forms of the ER, particularly the ER and ERß1 isoforms, which have similar, high affinities for 17ß estradiol (Kuiper et al., 1998). In situ hybridization data indicate widespread distribution of ERß mRNA throughout much of the brain, including olfactory bulbs, cerebellum, and cerebral cortex (Kuiper et al., 1997,1998). Results from immunocytochemical studies for ERß indicate a more-restricted localization of detectable protein, although the antisera that are currently available do not always provide specific signals in some brain areas (see McEwen and Alves, 1999, for discussion). Recent evidence shows good agreement between ERß mRNA levels and ERß immunoreactivity with a polyclonal antibody to the C terminus of ERß (Shughrue and Merchenthaler, 2001). In particular, colocalization of ERß mRNA with cell nuclear ERß immunoreactivity was demonstrated in the rat cerebral cortex, paraventricular nuclei of the hypothalamus, and hypothalamic preoptic area (Shughrue and Merchenthaler, 2001). Other brain regions remain to be studied for such co-localization.
The introduction of 125I estrogen to label ER with a higher specific radioactivity has revealed the presence of binding sites not previously detected using 3H estradiol (Shughrue et al., 1999; Shughrue and Merchenthaler, 2000). In hippocampus, labeling was evident in the interneurons previously seen to contain ER by other methods, with higher concentrations in ventral hippocampus (Shughrue and Merchenthaler, 2000). However, the most important difference from 125I estrogen labeling of ER was the detection of label in pyramidal cells of CA1–CA3 in the ventral hippocampus. In parallel studies of ER and -ß mRNA, there was a similar dorsal-to-ventral gradient as that seen for 125I estrogen binding and the ER signal appeared to be stronger than that for ERß (Shughrue and Merchenthaler, 2000). Thus, the greater sensitivity of 125I estrogen labeling of ER reveals sites that may indicate locations of estrogen actions in hippocampal pyramidal cells, particularly in pyramidal cell nuclei of the ventral hippocampus.
ER and ERß are similar not only in affinity for a number of estrogens and estrogen antagonists (Kuiper et al., 1998) but also in their ability to regulate genes in which the estrogen response element (ERE) is the primary site of interaction (Paech et al., 1997). The major differences between ER and ERß concern their ability to regulate transcription via the AP-1 response element. With AP-1, estradiol 17ß activated transcription with ER, whereas it failed to activate transcription with ERß and was able to cause inhibition. In contrast, with AP-1, nonsteroidal estrogen antagonists such as tamoxifen activated transcription with ERß and did so to a lesser extent with ER (Paech et al., 1997).
ER and ERß can form heterodimers when expressed in the same cells, thus giving rise to additional possible variants as far as gene regulation (Pettersson et al., 1997). Thus far, endogenous colocalization of ER and ERß has been demonstrated in the hypothalamic preoptic area, bed nucleus of the stria terminalis, and medial amygdaloid nucleus (Hrabovszky et al., 1998) and probably exists in other brain regions, including midbrain raphe (see below).
Nonsteroidal estrogen antagonists exert agonist-like effects on some neurochemical or functional endpoints in the rat brain and antagonistic effects on others. Antagonistic effects for CI-628, a tamoxifen-like estrogen antagonist, were seen in terms of blockade of estrogen-induced progestin receptor induction and lordosis behavior (Roy et al., 1979; Meisel et al., 1987). Agonist-like effects of CI-628 were seen for induction of choline acetyltransferase in basal forebrain and repression of monoamine oxidase A in amygdala (Luine and McEwen, 1977). Recently, CI-628 was shown to block estrogen-induced synapse formation in the hippocampus without having any agonist-like effects (McEwen et al., 1999b; Brake et al., 2001).
One important implication of these findings concerning the mixed agonist and antagonist role of some estrogen antagonists is that nonsteroidal anti-estrogens, like CI-628 and possibly also tamoxifen and raloxifene, will not have uniformly agonistic or antagonistic effects on the diversity of actions that estrogens normally produce in the brain. This has implications for the therapeutic applications of such agents and requires a separate study of the actions of these agents on each endpoint of estrogen action.
Unfortunately, the molecular basis of these effects is not clear. Although anti-estrogens function as antagonists for ER and ERß via the ERE, these same anti-estrogens worked through the AP-1 response element to activate transcription via ERß also, to a lesser extent, via ER (Paech et al., 1997). Yet, with AP-1, estradiol 17ß activated transcription with ER, whereas it failed to activate transcription with ERß and was able to cause inhibition (Paech et al., 1997). Thus, to account for parallel agonist-like actions of estrogen antagonists, such as we have demonstrated for choline acetyltransferase and monoamine oxidase, it is necessary to postulate that ER is the receptor involved and that it uses the AP-1 response element where both estradiol and CI-628 can have agonistic-like actions.
B. NOVEL ESTROGEN ACTIONS VIA NON-NUCLEAR RECEPTORS
Rapid estrogen effects on neuronal excitability (Kelly et al., 1977; Nabekura et al., 1986) have been known for a number of years. Yet, only recently has this topic emerged in full force as an alternative aspect of estrogen action that involves interactions of ERs with second messenger systems and potentially novel types of ERs (Kelly and Wagner, 1999; Brinton, 2001; Kelly and Levin, 2001; Lee and McEwen, 2001).
The variety of nongenomic estrogen effects includes 1) rapid actions on excitability of neuronal and pituitary cells; 2) the activation by estrogens of cyclic AMP and mitogen-activated protein kinase (MAP kinase) pathways that affect activity of such targets as kainate and insulin-like growth factor-1 (IGF-1) receptors; 3) estrogen actions that involve modulation of G protein coupling and affect calcium currents and gonadotropin-releasing hormone (GnRH) release; 4) effects on calcium channels and calcium ion entry; and 5) protection of neurons from damage by excitotoxins and free radicals (Kelly and Wagner, 1999; Brinton, 2001; Kelly and Levin, 2001; Lee and McEwen, 2001).
For estrogen actions on some aspects of calcium homeostasis, certain aspects of second messenger systems, and some features of neuroprotection, a novel receptor mechanism is implicated in which stereospecificity for 17ß over 17 estradiol is replaced by a broader specificity for the 3 hydroxyl group on the A ring ( McEwen and Alves, 1999; Lee and McEwen, 2001). On the other hand, there is also evidence that ER and ERß are capable of participating in second messenger cascades involving second messenger activation and G protein coupling (Razandi et al., 1999; Kelly and Levin, 2001). Besides ER and ERß, membrane ERs have been reported on pituitary, uterine, ovarian granulosa cell, spermatozoa, testes, and liver cell membranes. However, these have been only partially characterized in binding studies and only in a few cases have been shown to be linked to signal transduction mechanisms (for a review, see McEwen and Alves, 1999; Kelly and Levin, 2001; Lee and McEwen, 2001).
Finally, estrogenic compounds protect nerve cells from damage by excitotoxins and free radicals in novel ways (McEwen and Alves, 1999; Lee and McEwen, 2001). In this realm are neuroprotective effects that appear to be mediated via classical genomic receptors, based upon the fact that they can be blocked by estrogen antagonists. But other actions are not blocked by these antagonists and appear to involve a novel mechanism in which estradiol 17 is as potent as estradiol 17ß (Green et al., 1997; Lee and McEwen, 2001). These actions of estrogens, albeit in 100-nM to micromolar concentrations, reduce the production of or actions of free radicals in causing cell damage and promoting cell death through apoptosis. Mitochondria are major targets of estrogen action. Estrogen effects stabilize mitochondrial membrane potentials, prevent adenosine triphosphate (ATP) depletion, and reduce the generation of oxygen free radicals (Mattson et al., 1997; Wang et al., 2001).
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III. Estrogen Actions Throughout the Central Nervous System |
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TOPABSTRACTI. IntroductionII. Intracellular Mechanisms of Estrogen...III. Estrogen Actions Throughout the...IV. Estrogen Actions on Midbrain Raphe...V. Estrogen Actions in Hippocampus re:...V. Possible Functional SignificanceVI. ConclusionsREFERENCES |
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Estrogens affect areas of the brain that are not primarily involved in reproduction, such as the basal forebrain cholinergic system, the hippocampus and cerebral cortex, the caudate-putamen, midbrain raphe and brainstem locus coeruleus, and the spinal cord. These systems are involved in a variety of estrogen actions on mood, locomotor activity, pain sensitivity, vulnerability to epilepsy, and attentional mechanisms and cognition (for a review, see McEwen and Alves, 1999).
Functional or structural sex differences exist in a number of these brain regions (Fischette et al., 1984; Kimura, 1992; Bazzett and Becker, 1994; Witelson et al., 1995). For example, developmentally programmed sex differences in hippocampal structure may help explain differences in the strategies that male and female rats use to solve spatial navigation problems (Williams and Meck, 1991). A similar sex difference in spatial problemsolving is reported in humans (Kimura, 1992). During the period of development when testosterone is elevated in the male, aromatase activity and ERs are transiently expressed in hippocampus. Recent data on behavior and synapse induction strongly suggest that this pathway is involved in the masculinization or defeminization of hippocampal structure and function.
In spite of the paucity of ER outside the hypothalamus, hypothalamic preoptic region, and amygdala, estrogens have effects on many other brain regions and neurochemical systems involved in a host of nonreproductive brain functions. The expression of ERß mRNA in many of these brain regions has raised the possibility of functional ERs in these brain areas. At the same time, the presence of a few ER-containing nerve cells has led to the discovery, for example in the hippocampus, that these few nerve cells can have powerful trans-synaptic effects on neighboring neurons. As will be discussed in detail below, treatment of ovariectomized rats with estradiol 17ß induces certain hippocampal neurons to form new synaptic connections with other nerve cells. These estrogen effects appear to be attributable, at least in part, to intracellular ER in inhibitory interneurons (see below). In addition, the rapidity and structure-activity profile of some of these effects have raised questions about the possible "nontraditional" and even nongenomic actions of estrogens in some brain regions. For example, actions of estrogens on dopaminergic activity in the corpus striatum and nucleus accumbens appear to be mediated by membrane actions in the absence of any documented expression of either ER or ERß in cell nuclei of these brain regions (Maus et al., 1990; Mermelstein et al., 1996).
Estrogen actions upon cholinergic, noradrenergic, serotonergic, and hypothalamic dopaminergic systems, on the other hand, are likely to be mediated by known nuclear intracellular ER or ERß (see McEwen and Alves, 1999, for summary). This will be decribed for the serotonin system. The spinal cord also has intracellular ER and ERß but the reported effects on nociception and analgesia do not directly relate to those receptor sites in enkephalin-expressing spinal neurons. Moreover, endothelial cells and at least some glial cells must be considered as targets for estrogen action that affect glucose uptake and mechanisms that support the replenishment of cell membranes and possibly also synaptogenesis and other forms of structural plasticity (see McEwen and Alves, 1999; McEwen et al., 2001, for summary). We now will examine two systems involving actions of estrogens on brain areas that are involved in many functions beyond those specifically concerned with reproduction, namely, the midbrain serotonin system and the hippocampus.
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IV. Estrogen Actions on Midbrain Raphe and Serotonin Receptors in Forebrain |
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TOPABSTRACTI. IntroductionII. Intracellular Mechanisms of Estrogen...III. Estrogen Actions Throughout the...IV. Estrogen Actions on Midbrain Raphe...V. Estrogen Actions in Hippocampus re:...V. Possible Functional SignificanceVI. ConclusionsREFERENCES |
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In primates, both ER and ERß are found in midbrain 5HT neurons and estrogens regulate tryptophan hydroxylase as well as progestin receptor expression (Bethea et al., 1999). In rats, ER is found in non-5HT neurons, where estrogen regulates expression of progestin receptors (Alves et al., 1998) but not expression of tryptophan hydroxylase (S.E. Alves, unpublished data). Sex differences are found in the ability of estrogen treatment to induce progestin receptors (Alves et al., 1998). In mice, both ER and ERß are present and functional in the midbrain. ER is expressed in 5HT neurons that also express progestin receptors (Alves et al., 2000). Yet, the ERKO mouse also shows estrogen induction of progestin receptors in midbrain raphe, implying that another ER, most likely ERß, is involved (Alves et al., 2000) (Figure 1).
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S binding (Mize et al., 2001) after treatment with estrogen in homogenates of hippocampus and frontal cortex. Estradiol 17ß (EC50 = 25 nM) showed a dose-dependent ability to decrease GTPS binding. This effect was mimicked by diethylstilbestrol but not by the less-potent estrogens, estradiol 17 and estriol, and was blocked by the estrogen antagonist, ICI 182780 (Mize et al., 2001). These results are consistent with the involvement of a non-nuclear form of ER or ERß, as discussed above. |
V. Estrogen Actions in Hippocampus re: Cognitive Function and Memory Processes |
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TOPABSTRACTI. IntroductionII. Intracellular Mechanisms of Estrogen...III. Estrogen Actions Throughout the...IV. Estrogen Actions on Midbrain Raphe...V. Estrogen Actions in Hippocampus re:...V. Possible Functional SignificanceVI. ConclusionsREFERENCES |
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One of the processes regulated by ovarian hormones is the cyclic formation and breakdown of excitatory synapses in the hippocampus (Woolley et al., 1990). This finding was surprising because the hippocampus is a brain region in which cell nuclear ERs are present in scattered inhibitory interneurons but not in principal neurons where synapse formation occurs (Weiland et al., 1997). Yet, the effects of ovarian hormones on synaptic turnover were as impressive in the hippocampus as those in the ventromedial hypothalamus (Carrer and Aoki, 1982; Frankfurt et al., 1990; Calizo and Flanagan-Cato, 2000), a classic estrogen target area of the brain for female sexual behavior (Pfaff, 1980).
A. MECHANISM OF EXCITATORY SYNAPSE FORMATION IN THE HIPPOCAMPUS
Estrogen treatment increases dendritic spine density on CA1 pyramidal neurons. As observed by electron microscopy, treatment of ovariectomized adult rats with estrogen also induces new synapses on spines and not on dendritic shafts of CA1 neurons (Woolley and McEwen, 1992). Estrogen did not effect dendritic length or branching (Gould et al., 1990; Woolley et al., 1990; Woolley and McEwen, 1992). Progesterone treatment acutely enhances spine formation. But, over a 12- to 24-hour period, progesterone caused the downregulation of estrogen-induced synapses (Gould et al., 1990; Woolley and McEwen, 1993).
Estrogens do not act alone and, in fact, ongoing excitatory neurotransmission is required for synapse induction, as shown by the finding that antagonists of NMDA receptors block estrogen-induced synaptogenesis on dendritic spines in ovariectomized female rats (Woolley and McEwen, 1994). Because estrogen treatment increases the density of NMDA receptors in the CA1 region of the hippocampus (Weiland, 1992; Woolley et al., 1997), the activation of NMDA receptors by glutamate is an essential factor in causing new excitatory synapses to develop.
Spines are occupied by asymmetric, excitatory synapses and are sites of Ca2+ ion accumulation and contain NMDA receptors (Horner, 1993). NMDA receptors are expressed in large amounts in CA1 pyramidal neurons and can be imaged by conventional immunocytochemistry as well as by confocal imaging, in which individual dendrites and spines can be studied for co-localization with other markers (Gazzaley et al., 1996). Confocal microscopic imaging showed that estrogen treatment upregulates immunoreactivity for the largest NMDA receptor subunit, NR1, on dendrites and cell bodies of CA1 pyramidal neurons, whereas NR1 mRNA levels did not change after estrogen treatment that induces new synapses (Gazzaley et al., 1996). This suggests the possibility that NR1 expression is regulated post-transcriptionally by estrogen.
Recent evidence indicates that in young female rats, estrogen induction of NR1 is proportional to the induction of new spines, so that NMDA receptor density per spine is not increased; however, in the aging female rat, there is NR1 induction without an increase in dendritic spines (Adams et al., 2001) (Figure 3). This might make the aging hippocampus more vulnerable to excitotoxic damage, for example, by stroke or seizures.
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There are a number of presynaptic molecular markers of mature synapses that can be used in studies of synapse formation (McEwen et al., 2001). GAP43 is a marker of the growth cone and has been shown to increase in the hypothalamus after estrogen treatment; however, no studies of this type have been done on the hippocampus. SNAP-25 is a marker of synaptic vesicles, as are syntaxin, synaptotagmins, synaptoporin, synaptophysin, and the synapsins. Although mRNAs for these proteins are most likely found in neuron cell bodies, growth cones of hippocampal neurons in culture have been reported to have mRNAs for proteins such as GAP43 and Arc and perhaps other presynaptic proteins; these can be translated in the growth cone (Crino and Eberwine, 1996).
C. APPLICATION OF RADIOIMMUNOCYTOCHEMISTRY TO STUDY SYNAPSE FORMATION AND MATURATION
The methods used to assess synapse formation (i.e., Golgi staining, dye filling of cells, electron microscopy) are all labor intensive and time consuming and do not provide information about the underlying molecular events. Radioimmunocytochemistry is a method for assessing the locally expressed levels of synaptic and spine proteins using a primary antibody and a radioactive secondary antibody, then assessing levels of radioactivity using quantitative autoradiography. This procedure has not only confirmed the anatomical methods for assessing spine synapse formation but has also added a new dimension by providing insights into estrogen-induced increases in proteins that characterize presynaptic terminals and spines.
Figure 5 shows the results of the first study, using synaptophysin and syntaxin as presynaptic markers and spinophilin as a spine marker (Brake et al., 2001). Estrogen treatment was conducted exactly as in previous studies using the Golgi method and the estrogen antagonist, CI 628, was used to block estrogen actions (McEwen et al., 1999a). Estrogen treatment induced both pre- and postsynaptic markers in the stratum oriens and stratum radiatum of the CA1 region, location of the spine synapses (Brake et al., 2001). The magnitude of the increases corresponded very well to the magnitude of the changes in spine density seen with the Golgi method (Woolley et al., 1997; McEwen et al., 1999a). These effects were blocked by CI-628, which had no agonist effects by itself, and this finding agreed with the Golgi results (McEwen et al., 1999a). One unique finding with radioimmunocytochemistry is the estrogen-induced increase in spinophilin immunoreactivity in the hilus of the dentate gyrus and in the stratum lucidum of CA3, neither of which is accompanied by increases in the presynaptic markers, synaptophysin, and syntaxin (Brake et al., 2001). This suggests that there may be a process of synapse maturation taking place that reflects expression of spinophilin in the absence of any estrogen-induced changes in presynaptic proteins. Further studies are needed to confirm this interpretation.
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and ERß mRNA by in situ hybridization (Shughrue and Merchenthaler, 2000; McEwen et al., 2001). Instead, immunocytochemistry for ER showed cell nuclear ER in sparsely distributed interneurons in the CA1 region as well as other regions of Ammon’s horn and dentate gyrus, with greater density in the ventral than dorsal hippocampus (McEwen and Alves, 1999). As far as ERß immunoreactivity, an antibody generated at the C-terminal end of the receptor revealed only weak labeling of cell nuclei, particularly in the ventral hippocampus, and some staining of dendrites of pyramidal cells (Shughrue and Merchenthaler, 2001).
Autoradiography with 125I estrogen to label ER with a higher-specific radioactivity showed binding sites not previously detected in hippocampus using 3H estradiol (Shughrue and Merchenthaler, 2000). Besides the interneurons previously seen to contain ER by other methods, labeling with 125I estrogen was found in CA1–CA3 pyramidal cell nuclei in ventral hippocampus. A similar dorsal-to-ventral gradient was seen for ER and ERß mRNA and 125I estrogen binding. The ER signal appeared to be stronger than that for ERß (Shughrue and Merchenthaler, 2000). Thus, the greater sensitivity of 125I estrogen labeling of ER reveals sites that may indicate locations of estrogen actions in hippocampal pyramidal cells, particularly in the ventral hippocampus. A recent developmental study of ER in the rat hippocampus is consistent with this and suggests that, early in development, more pyramidal cells may have nuclear ER than in the adult (Solum and Handa, 2001). Recent data with radioimmunocytochemistry have shown much stronger estrogen effects on synapse and spine protein levels in ventral, compared to dorsal hippocampus (Bulloch et al., 2000).
E. CELL-CULTURE MODEL OF SYNAPSE FORMATION
It has been possible to study estrogen-induced synapse formation in cell cultures of hippocampal neurons. In this model, estrogen induces spines on dendrites of dissociated hippocampal neurons in cell culture by a process that is blocked by an NMDA receptor antagonist and not by an AMPA (alpha-amino-3-hydroxy-5-methylisoxasole proprionic acid)/kainate receptor blocker (Murphy and Segal, 1996). Furthermore, estrogen treatment was found to increase expression of phosphorylated cyclic AMP response binding protein (CREB). A specific antisense to CREB prevented both the formation of dendritic spines and the elevation in phosphoCREB immunoreactivity (IR) (Murphy and Segal, 1997).
The cellular location of ER in the cultures, resembling the in vivo localization, was in putative inhibitory interneurons (i.e., glutamic acid decarboxylase (GAD)-immunoreactive cells) that constituted around 20% of total neuronal population. Estrogen treatment caused decreases in GAD content and the number of neurons expressing GAD. Mimicking this decrease with an inhibitor of gamma aminobutyric acid (GABA) synthesis, mercaptopropionic acid, caused an upregulation of dendritic spine density, paralleling the effects of estrogen (Murphy et al., 1998a). Thus, estrogen-induced synapse formation may involve the suppression of GABA inhibitory input to the pyramidal neurons where the synapses are being generated (Figure 6).
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F. NON-NUCLEAR ESTROGEN RECEPTORS
As compelling as the role of estrogen-regulated GABA input appears to be to the mechanism of synapse formation, we were not satisfied that there was no additional role for estrogen actions in the pyramidal neurons themselves. Given the increasing evidence for such a mechanism, it seemed plausible that, besides the indirect, trans-synaptic mechanism described above, local signaling by estrogen might be involved. This hypothesis was stimulated by a seminal study that ER and ERß into Chinese hamster ovarian cells found that both ERs are expressed in a form that couples to second messenger systems that are stimulated by estrogen and blocked at least partially by nonsteroidal estrogen antagonists (Razandi et al., 1999). Previous studies had indicated that non-nuclear ERs can be seen at the light microscopic level in cultured cells (Clarke et al., 2000) and also at the electron microscopic (EM) level in hypothalamus (Blaustein et al., 1992). The proliferation of articles on non-nuclear actions of estrogen via membrane ER and membrane-associated ER (Kelly and Levin, 2001) has reinforced the importance of investigating non-nuclear actions of estrogens in the hippocampus.
Electron microscopy was used to examine ER localization in rat hippocampal formation (Milner et al., 2001) utilizing four antibodies to different parts of the ER structure, two polyclonal and two monoclonal. The specificity of these antibodies was determined by preabsorption with the full-length ER protein, which abolished labeling in all sites examined, both nuclear and non-nuclear. We were able to see at the EM level the cell nuclear labeling seen by light microscopy in some GABA interneurons. In addition, some pyramidal and granule neuron perikarya have small amounts of ER IR in the nuclear membrane, which is consistent with a recent report that 125I estradiol labels a small number of estrogen-binding sites in cell nuclei of hippocampal principal cells (Shughrue and Merchenthaler, 2000).
In stratum radiatum of CA1, around 50% of the ER-IR profiles were found in unmyelinated axons and axon terminals containing small synaptic vesicles. This is of potential functional relevance, given findings that estrogen can influence neurotransmitter release (see McEwen et al., 2001, for references). The synaptic ER-IR was found in terminals that formed both asymmetric and symmetric synapses on dendritic shafts and spines, suggesting that both excitatory and inhibitory transmitter systems are associated with ER (Milner et al., 2001).
Around 25% of the ER IR was found in dendritic spines of principal cells, where it often was associated with spine apparati and/or post-synaptic densities, suggesting that estrogen might act locally to regulate calcium availability, phosphorylation, or protein synthesis. Finally, the remaining 25% of ER IR was found in astrocytic profiles, often located near the spines of principal cells.
While these findings corroborate existing evidence for an indirect GABA-ergic mediation of estrogen actions (Murphy et al., 1998a; Rudick and Woolley, 2000), the close association between the ER-IR and dendritic spines supports a possible local, nongenomic role for this ER in regulation of dendritic spine density via second messenger systems. Initial in vivo and in vitro studies in hippocampus of one second messenger pathway, the phosphorylation of CREB, have indicated that estrogen has rapid effects that are evident within as little as 15 minutes to increase phosphoCREB immunoreactivity in cell nuclei of hippocampal pyramidal neurons (S. Lee, S. Alves, B. McEwen, unpublished data). One pathway by which CREB phosphorylation may occur involves the phosphoinositol-3 (PI3) kinase, or Akt, system (Datta et al., 1999). Studies are underway to try to connect these events together in the early actions of estrogen on hippocampal neurons that precede the induction of synapse formation. We next consider some of the cellular and molecular events associated with the formation of synapses in which estrogen actions may be involved.
G. DENDRITIC mRNA TRANSPORT AND PROTEIN SYNTHESIS
The finding of non-nuclear ER in dendritic spines compelled us to consider sites and mechanisms whereby estrogens could regulate the process of synapse formation via post-transcriptional mechanisms. Protein synthesis is likely to be an essential component of de novo synapse formation. Neurons have at least three strategies for activity-dependent regulation of protein synthesis and targeting of those proteins to pre- and postsynaptic sites (Tiedge et al., 2001). First, there is translation of mRNA in the cell soma and trafficking of proteins to "tagged" synapses. Second is transport of mRNA into the dendrites or growth cones and local translation into protein on polyribosomal clusters such as are found at the base of spines. The third strategy is local regulation of the translation of transported mRNAs (Tiedge et al., 2001).
Dendrites contain transported mRNAs for gene products such as MAP-2, CaMKII, NMDA R1 subunit, Arc, GAP-43, and BC1 (Gao, 1998). One feature of the regulation of translation is that the dendritic mRNAs are deficient in poly A; therefore, the regulation of polyadenylation by cytoplasmic polyadenylation element binding protein (CPEP) is able to rapidly activate translation (Wells et al., 2000). Moreover, other regulatory points such as the initiation of the translation process via regulatory factors are subject to second messenger-stimulated phosphorylation (Gingras et al., 1999). These are currently under investigation in our laboratory as far as possible regulation by estrogen.
H. A MODEL OF ESTROGEN ACTION INVOLVING GENOMIC AND NONGENOMIC ERs
The results summarized above have led us to propose a testable, working model (Figure 7) that delineates possible sites of estrogen action in relation to the location of nuclear and non-nuclear ERs. Although this model pertains to ER because we know more about its distribution, further studies of ERß may reveal that it is present in non-nuclear as well as cell nuclear sites within the hippocampus and may participate in some of the processes outlined in Figure 7. According to our model, ER in the dendritic spine may be associated with the activation of mRNA translation from polyribosomes (Tiedge et al., 2001) or endomembrane structures found in spines (Pierce et al., 2000). In addition, other second messenger signaling effects might include the phosphorylation of neurotransmitter receptors or ion channels. ERs in certain presynaptic terminals might modulate neurotransmitter release or reuptake (see McEwen et al., 2001, for references). Moreover, ER-mediated activation of second messenger systems in dendritic spines and presynaptic endings might lead to retrograde signal transduction back to the cell nucleus, perhaps via Akt or CREB, providing another pathway through which estrogen could regulate gene expression. As indicated at the bottom right of Figure 7, we consider that these postulated actions of estrogen operate synergistically with the actions of estrogen via nuclear receptors in interneurons that modulate the inhibitory tone upon the CA1 pyramidal neurons where synapse formation occurs.
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V. Possible Functional Significance |
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TOPABSTRACTI. IntroductionII. Intracellular Mechanisms of Estrogen...III. Estrogen Actions Throughout the...IV. Estrogen Actions on Midbrain Raphe...V. Estrogen Actions in Hippocampus re:...V. Possible Functional SignificanceVI. ConclusionsREFERENCES |
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Besides affecting neuronal activity in hippocampus, estrogen treatment affects hippocampal-dependent learning and memory. In the natural estrous cycle of the female rat, a recent study has utilized a delayed matching-to-place task in female rats to show a close parallel between the temporal conditions by which estrogen improves memory and the conditions for it to induce new excitatory synaptic connections in the hippocampus (McEwen et al., 2001). Moreover, estrogen treatment of ovariectomized female rats has been reported to improve acquisition on a radial maze task as well as in a reinforced T-maze alternation task (Fader et al., 1998; Daniel et al., 1999). Furthermore, sustained treatment is reported to improve performance in a working memory task (O’Neal et al., 1996) as well as in the radial-arm maze (Luine et al., 1998; Daniel et al., 1999). Finally, the effects of estrogen replacement in rats are reminiscent of the effects of treatment in women whose estrogen levels have been suppressed by a gonadotrophin-releasing hormone agonist used to shrink the size of fibroids prior to surgery (Sherwin and Tulandi, 1996).
In addition to the delayed effects of estrogens in hippocampus, estrogens and some form of ER are involved in local signaling within neurons. Among the possible targets of local signaling is the translation of RNAs found in dendrites of hippocampal and other neurons. There are at least three other targets for local signaling by estrogens. They are 1) the rapid activation of kainate-induced ion currents via a G protein-coupled ER that is present in ERKO mice and is insensitive to nonsteroidal estrogen antagonists (Gu et al., 1999); 2) the suppression of calcium ion currents that is mimicked by a nonsteroidal estrogen antagonist (Mermelstein et al., 1996); and 3) rapid actions of estradiol on NMDA receptor activity and LTP (Teyler et al., 1980; Foy et al., 1999).
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TOPABSTRACTI. IntroductionII. Intracellular Mechanisms of Estrogen...III. Estrogen Actions Throughout the...IV. Estrogen Actions on Midbrain Raphe...V. Estrogen Actions in Hippocampus re:...V. Possible Functional SignificanceVI. ConclusionsREFERENCES |
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. What all of this means is that, besides the classical genomic actions of estradiol that have been studied for over 40 years, the molecular mechanisms of estrogen action are likely to involve many pathways not ordinarily considered, in which indirect genomic activation may occur as a consequence of second messenger activation.
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TOPABSTRACTI. IntroductionII. Intracellular Mechanisms of Estrogen...III. Estrogen Actions Throughout the...IV. Estrogen Actions on Midbrain Raphe...V. Estrogen Actions in Hippocampus re:...V. Possible Functional SignificanceVI. ConclusionsREFERENCES |
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) gene-disrupted mice.
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