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Endocrinology Vol. 140, No. 3 1044-1047
Copyright © 1999 by The Endocrine Society

ARTICLES

Inhibition of Dendritic Spine Induction on Hippocampal CA1 Pyramidal Neurons by a Nonsteroidal Estrogen Antagonist in Female Rats1

Bruce S. McEwen, Patima Tanapat and Nancy G. Weiland

Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, Rockefeller University, New York, New York 10021; and the Department of Psychology, Princeton University (P.T.), Princeton, New Jersey 08540

Address all correspondence and requests for reprints to: Bruce S. McEwen, Ph.D., Rockefeller University, Box 165, 1230 York Avenue, New York, New York 10021. E-mail: mcewen{at}rockvax.rockefeller.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Estrogens regulate the formation of excitatory synaptic connections in the hippocampus of female rats. Because the adult hippocampus has a very low concentration of intracellular estrogen receptors, it is unclear whether a conventional genomic mechanism is involved. Nonsteroidal estrogen antagonists are useful tools to study estrogen action because they can provide pharmacological data in favor of a particular pathway of estrogen action and evidence against other pathways. To investigate the role of intracellular estrogen receptors in the estrogen induction of synapse formation, we took advantage of previous studies in which we had shown that an estrogen antagonist, CI-628, enters the brain and blocks estrogen induction of progestin receptors to study whether the same antagonist would either mimic or block effects of estradiol to induce excitatory spine synapses. Using silver impregnation of neurons by the single section Golgi technique and morphometric analysis, we found that CI-628 effectively prevented estrogen induction of spines on CA1 pyramidal neurons, without having any agonist effects of its own. This result is consistent with an action of estradiol via intracellular estrogen receptors that are known to be expressed by interneurons within the hippocampus.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
OVARIAN steroids regulate the formation of excitatory synapses on dendritic spines (1, 2). This was first identified by Golgi staining and subsequently verified by electron microscopy to show directly an increase in synapse density (3) and more recently by dye filling to reveal dendritic spines by another visualization method (4). Estrogen treatment increases spine and spine synapse density on apical and basal dendrites of CA1 pyramidal neurons of ovariectomized adult female rats and does so within several days (1, 2, 3). Estrogen receptors (ERs) are present in very low levels in the adult hippocampus (5, 6), and they have been localized by steroid autoradiography (7) and immunocytochemistry for the ER{alpha} within cells that resemble interneurons in the CA1 stratum oriens and radiatum (8, 9). CA1 pyramidal neurons, on which the synapse formation is occurring, do not have detectable levels of ERs by either of these methods. In view of possible nongenomic mechanisms of estrogen actions, and considering that intracellular ER levels might be too low for detection by present methods, one strategy to identify the intracellular mechanism of synapse induction in hippocampus is to use nonsteroidal estrogen antagonists that bind to the intracellular ER, but do not block the rapid membrane effects (10, 11). Antiestrogens also have another use, namely to discriminate between the response elements that the ER uses to activate transcription. Nonsteroidal antiestrogens bind to ERs and activate transcription via activating protein-1 (AP-1) response elements (12) while blocking transcriptional activation through the classical estrogen response element (ERE) and not producing any agonist effect via this pathway (13). Nonsteroidal antiestrogens such as tamoxifen and CI628 block transcriptional activation of the ER via both the ER{alpha} and -ß and the classical ERE (13, 14). It is presumably through this pathway that antiestrogens of the tamoxifen type, including CI-628, reduce estrogen induction of progestin receptors in hypothalamus as well as activation of sexual behavior in female rats while at the same time demonstrating a low level of agonist activity (15, 16). To investigate the role of intracellular ERs in estrogen induction of synapse formation, we took advantage of previous studies in which we and others had shown that estrogen antagonists block estrogen induction of progestin receptors and lordosis behavior (15, 16), and we used one of these antagonists that crosses the blood-brain barrier, CI-628 (15, 16, 17), to study whether it would either mimic or block effects of estradiol to induce excitatory spine synapses.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animal treatments
Twenty-one adult female Sprague-Dawley rats (Charles River Laboratories, Inc., Lexington, MA; 180–200 g) were ovariectomized under Metofane anesthesia. Six days after ovariectomy, they were given sc injections of either CI628 (nitromiphene citrate [{alpha}-(4-pyrrolidinoethoxyl)phenyl-4-methoxy-{alpha}-nitrostilbene]; 10 mg/kg BW; n = 11; Parke-Davis, Ann Arbor, MI) or the vehicle (vehicle 1, sterile distilled water; n = 10) for 3 consecutive days at 1400–1500 h. Half of the rats in the CI628 group and half of the rats in the vehicle group were injected sc with ß-estradiol benzoate (EB; 10 µg/kg BW; Sigma Chemical Co., St. Louis, MO) on the second and third days, whereas the remaining rats in each group were injected with the sesame oil vehicle (vehicle 2). As a result, there were four treatment groups: 1) both vehicles (n = 5), 2) vehicle 1 plus EB (n = 5), 3) vehicle 2 plus CI-628 (n = 5), and 4) EB plus CI-628 (n = 6). Twenty-four hours after the last injection of 17ß-estradiol benzoate or oil, the rats were deeply anesthetized and transcardially perfused with 4.0% paraformaldehyde in 0.1 M phosphate buffer containing 1.5% saturated picric acid. The brains were removed from the skulls and postfixed overnight at 4°C in the perfusate before Golgi impregnation.

All animal experimentation was conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals (NIH Publication 85–23, revised 1985). The animals were maintained on a 14-h light, 10-h dark cycle and provided with food and water ad libitum.

Golgi impregnation
One hundred-micron coronal sections were cut in a bath containing 3.0% potassium dichromate on an oscillating tissue slicer. The sections were then incubated overnight in 3.0% potassium dichromate. On the following day, the sections were rinsed twice in double distilled water and mounted onto glass slides. After all of the excess water around the sections was removed, glass coverslips were placed over the section and glued in place with Krazy Glue (Borden Inc., Columbus, OH). The slide assemblies were then incubated in a Coplin jar containing 1.5% silver nitrate for 2 nights in the dark. The slide assemblies were removed from the silver nitrate, and the coverslips were detached with a razor blade. The sections were rinsed free floating in double distilled water, dehydrated in a series of ethanols, cleared with Americlear (Baxter Diagnostics, Deerfield, IL), mounted onto gelatinized slides, and then coverslipped under Permount (Fisher Scientific, Pittsburgh, PA).

Data analysis
All of the slides were coded before quantitative analysis, and the code was not broken until the analysis was completed. For each animal, six cells from the CA1 pyramidal region that exhibited dark and consistent impregnation throughout the cell body and dendritic tree were selected for analysis. For each of the cells selected, the number of spines on at least three segments of the apical dendritic tree was determined (see Fig. 1Go). No primary dendrites were analyzed, and all of the segments selected for analysis were 1) 10 µm or greater in length, 2) located 150–200 µm from the cell body, and 3) not located at the terminal of a dendrite. Camera lucida tracings were made of each of the dendritic segments, and the length was determined using a Zeiss Interactive Digitizing Analysis System. The data were expressed as spine densities (number of spines per 10 µm), the mean values for each animal were determined, and the data were subjected to one-way ANOVA with Scheffe’s F test post-hoc comparison.



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  		Figure 1. Camera lucida drawing of a hippocampal CA1 pyramidal neuron showing the locations of dendritic segments that were analyzed for spine density as described in Materials and Methods.

 

   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Ovariectomized female rats received EB, CI-628, or their combination, as described above. Their brains were processed for Golgi staining, and dendritic spine density was evaluated on apical dendrites of CA1 pyramidal neurons (Fig. 1Go) as in previous studies (see introduction).

As summarized in Fig. 2Go, the administration of CI628 alone had no effect on spine density, whereas EB produced a highly significant increase in spine density that was incompletely, but very significantly, blocked by the combination of CI-628 and EB treatment. Administration of CI628 alone had no significant effect on spine density.



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  		Figure 2. Spine density on CA1 pyramidal neurons is expressed as spines per 10 µm length on secondary dendrites that were greater than 10 µm in length and located 150–200 µm away from the cell body. Six CA1 neurons fulfilling the criteria described inMaterials and Methods were analyzed for each rat brain. The number of rats per group were six for CI628 plus EB and five for each of the other treatments. The error bars show the SEM; this is based upon the mean and variance calculated across animals, with data for the six neurons of each animal in a treatment compiled into a single average. Statistical analysis of data revealed that there was an overall treatment effect (P < 0.0001, by one-way ANOVA). A Tukey HSD post-hoc comparison revealed a clear estrogen induction of spines, in which the group receiving ovariectomy and estrogen treatment (ovx + E) was different from each of the other groups (P < 0.001). Moreover, CI628 partially blocked the effect of estrogen, in that values in the group receiving ovariectomy, estrogen, and CI628 (ovx + E + CI) were significantly elevated compared with those in the group receiving only ovariectomy (OVX; P < 0.01) and significantly less that the group receiving ovariectomy and estrogen (ovx + E; P < 0.001). There was no agonist effect of CI628 by itself on spine density (P = 0.92).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Estrogen induction of dendritic spines and spine synapses in the hippocampus is a rapid form of structural plasticity within the adult brain. The spine density changes during the estrous cycle of the female rat, being highest on the day of proestrus when ovulation and sexual behavior occur and lowest the next day, the day of estrus, when the system resets itself for another cycle (18). These variations resemble those described for synapses in the ventromedial hypothalamus (19, 20, 21). Electron microscopy was used to show that increases in dendritic spine density are paralleled by increases in profiles corresponding to spine synapses on CA1 pyramidal neurons, whereas the density of shaft synapses does not change (3). Concerning the mechanism of synaptic turnover, we found that blocking N-methyl-D-aspartate (NMDA) receptors during estrogen treatment prevents synapse induction (22), whereas the down-regulation of synapses between the days of proestrus and estrus was blocked by Ru486, an antagonist of progestin and glucocorticoid receptors (2). The disappearance of synapses after estrogen withdrawal is very slow, and progesterone treatment accelerates synapse down-regulation (2). Thus, it appears that excitatory amino acid neurotransmission is critical for synapse induction by estradiol, and estrogen-inducible progestin receptors may be the key to terminating the up-regulated synapses.

We used a specific dose of sc CI628 and a treatment regimen that we and others previously found to block estrogen induction of progestin receptors in the hypothalamus (15, 16), thus providing a benchmark for evaluating the effects of CI628 on spine synapse induction by EB. Our present results show that CI-628 blocked the induction by EB of dendritic spines on CA1 pyramidal neurons, and that CI-628 by itself has no effect on spines. This regimen of CI628 produced an incomplete, albeit highly significant, antagonism of the estrogen effect on spine induction, which was of a similar magnitude to the partial, but highly significant, blockade of progestin receptor induction reported previously (15). This result is consistent with the involvement of the ERE rather than the AP-1 site, as progestin receptor induction involves the ERE (23).

Nonsteroidal antiestrogens such as tamoxifen and CI628 block transcriptional activation of the ER via both the ER{alpha} and -ß and the classical ERE (13, 14). It is presumably through this pathway that antiestrogens of the tamoxifen type, including CI-628, reduce estrogen induction of progestin receptors in the hypothalamus as well as activation of sexual behavior in female rats, while at the same time demonstrating a low level of agonist activity (15, 16). However, it should also be noted that there are other reported estrogen-like actions of CI-628 in brain, namely to reduce monoamine oxidase activity in amygdala and to increase choline acetyltransferase activity in preoptic area-basal forebrain (17). These may involve a different pathway, possibly involving the ERß and AP-1 site (13, 14), as will be discussed below.

Had CI-628 not blocked the estrogen effects to induce spines on CA1 pyramidal neurons, there would be reason to suspect such a mechanism, a response element other than the ERE, or a nongenomic membrane action. This is because some antiestrogens such as tamoxifen bind to ER and activate transcription via the AP-1 response element (12, 14). Moreover, another response element, the raloxifene response element (24), has been described for the agonist-like effects of the tamoxifen-like nonsteroidal antiestrogen, raloxifine. According to a recent report (14), ER{alpha} and ERß show opposite agonist/antagonist profiles via the AP-1 site, with estradiol activating transcription and antagonists blocking transcription via ER{alpha}, whereas the opposite is true for ERß (14). According to this result, an ERß-AP-1 interaction in the hippocampus would have meant that CI-628 would have induced synapse formation and EB treatment would have blocked it, which clearly did not occur.

Regarding the ER{alpha} and -ß in hippocampus, we mapped the ER{alpha} by immunocytochemistry and found it to be expressed in scattered interneurons (9) that are known to interact with the CA1 pyramidal neurons where synapse induction occurs (25). We found no evidence of immunoreactivity for the ERß in CA1 hippocampal neurons (Weiland, N. G., S. E. Alves, and G. N. Lopez, unpublished observations), although under certain conditions the ERß may be present in the CA2 pyramidal neurons (26). The failure to find any [3H]estradiol-derived radioactivity in CA1 pyramidal neurons by quantitative autoradiography, under conditions that reveal [3H]estradiol retention in the interneuron population (7) in which we see ER{alpha} by immunocytochemistry (8, 9), argues against there being large amounts of either ER{alpha} or -ß in CA1 pyramidal neurons.

That we found an antagonist effect of the tamoxifen-like antiestrogen, CI628, on estrogen-induced synaptogenesis also argues against involvement of several known nongenomic, membrane actions of estradiol. The two known membrane actions of estradiol involve modulation of the {alpha}-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor and of calcium currents, respectively. Tamoxifen failed to block the direct effects of estrogen on the AMPA receptor (27) and had agonist-like effects, mimicking estrogen’s actions, to inhibit calcium currents in striatal neurons (10). Thus, the two known nongenomic membrane actions of estrogens do not have the pharmacological characteristics as far as the effects of an estrogen antagonist vs. estrogen that would have implicated them in spine induction on CA1 pyramidal neurons.

Not every estrogen antagonist gets into the brain. ICI182780 (28) does not enter the brain (Wakeling, A., personal communication), and RU58688 has been reported to enter the brain only at high doses and with difficulty (29, 30). In contrast, CI-628 enters the brain, judging from its reported ability to block in vivo cell nuclear uptake and retention of [3H]estradiol in hypothalamus, preoptic area, and amygdala by 87% at 18 h after CI-628 treatment (17) as well as by the incomplete, but highly significant, blockade of both progestin receptor induction (15, 16) and dendritic spines (this study) and the induction of estrogen-like changes in brain monoamine oxidase and choline acetyltransferase (17). In view of the results of the present study, failure of some antiestrogens to enter the brain may be advantageous to avoid possibly deleterious estrogen-blocking effects in the central nervous system of agents that can cause potentially beneficial estrogen-like peripheral effects, such as promoting bone calcification and lowering serum lipid levels (31).

Concerning target genes that may mediate the actions of estradiol on synaptogenesis, NMDA receptors are known to be up-regulated by estradiol in the CA1 region of the hippocampus (4, 32, 33) and to be required for estrogen-induced synaptogenesis (22). The phosphorylation of cAMP response element-binding protein is also reported to be up-regulated by estrogen treatment in a cell culture model of synaptogenesis (34), and recent evidence from our laboratory indicates that estrogen induction of cAMP response element-binding protein phosphorylation is blocked by CI-628 treatment in a similar cell culture model (Kimonides, V., C. Li, and B. S. McEwen, unpublished). Thus, there are several specific estrogen-regulated gene products upon which to target future studies of estrogen-induced synapse formation both in vitro and in vivo.

Given the location of estrogen receptors in interneurons (9), what role might they play in estrogen-induced synaptogenesis on CA1 pyramidal neurons? First, it should be noted that basket cell interneurons in the hippocampus have large fields of innervation that may include as many as 1500 pyramidal neurons (25, 35); thus, a single estrogen-sensitive interneuron is very likely to have a powerful influence on many pyramidal neurons. Second, given this type of widespread influence, the most plausible explanation for the transneuronal influence has been offered by Murphy and Segal (36), who showed that estrogen treatment causes a transient reduction in the expression of {gamma}-aminobutyric acid in estrogen-sensitive interneurons; they have proposed that this might create a period of disinhibition during which increased expression of NMDA receptors would be able to occur on the pyramidal neurons. As noted above, NMDA receptors are up-regulated by estrogen treatment on CA1 pyramidal neurons (4, 32, 33), and blockade of NMDA receptors prevents synaptogenesis (22), although the exact pathway for NMDA receptors to facilitate synaptogenesis is not known.

In conclusion, CI-628 blocks estrogen-induced spine formation on CA1 pyramidal neurons, and this together with other information summarized above argues strongly for mediation via the ERE by the ER{alpha} that is found on interneurons in the hippocampal formation. Additional approaches, using ER knockout animals and other estrogen antagonists that enter the brain, are required to further support this conclusion.


   Acknowledgments
 
We acknowledge with appreciation the supply of CI-628 by Parke-Davis (Ann Arbor, MI).


   Footnotes
 
1 This work was supported by NIH Grant NS-07080. Back

Received June 23, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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D. B. Dubal, H. Zhu, J. Yu, S. W. Rau, P. J. Shughrue, I. Merchenthaler, M. S. Kindy, and P. M. Wise
Estrogen receptor alpha , not beta , is a critical link in estradiol-mediated protection against brain injury
PNAS, February 13, 2001; 98(4): 1952 - 1957.
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