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Endocrinology Vol. 145, No. 3 1042-1045
Copyright © 2004 by The Endocrine Society

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Dehydroepiandrosterone Increases Hippocampal Spine Synapse Density in Ovariectomized Female Rats

Tibor Hajszan, Neil J. MacLusky and Csaba Leranth

Departments of Obstetrics and Gynecology (T.H., C.L.) and Neurobiology (C.L.), Yale University School of Medicine, New Haven, Connecticut 06520; Laboratory of Molecular Neurobiology (T.H.), Biological Research Center, Hungarian Academy of Sciences, H-6726 Szeged, Hungary; and Center for Reproductive Sciences (N.J.M.), Columbia University Medical School, New York, New York 10032

Address all correspondence and requests for reprints to: Csaba Leranth, M.D., Ph.D., Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar Street, FMB 313, New Haven, Connecticut 06520-8063. E-mail: csaba.leranth{at}yale.edu.

Abstract

This study tests the hypothesis that dehydroepiandrosterone (DHEA) stimulates formation of hippocampal CA1 spine synapses in ovariectomized rats. Subcutaneous injections of DHEA (1 mg/d for 2 d) increased CA1 spine synapse density by more than 50% compared with vehicle-injected animals. The effect of DHEA on CA1 synapse density was abolished by pretreatment with the nonsteroidal aromatase inhibitor, letrozole. DHEA treatment, with or without letrozole, had no detectable uterotrophic effect. These observations are consistent with the hypothesis that DHEA treatment may be capable of reversing the decline in hippocampal spine synapse density observed after loss of ovarian steroid hormone secretion. The blockade of the synaptic response to DHEA by letrozole, despite the lack of a uterotrophic response to this steroid, suggests that the hippocampal response to DHEA may be mediated via aromatization in the brain.

IN HUMAN BEINGS, dehydroepiandrosterone (DHEA) is the most abundant androgen secreted by the adrenal glands. Circulating levels of DHEA and DHEA sulfate peak during early adulthood and then decline, to less than 30% of maximal by the sixth decade of life (1, 2). The properties of DHEA are consistent with a physiological role for this steroid as a precursor for bioactive androgens and estrogens (reviewed in Ref. 2). This has led to the hypothesis that DHEA may be useful in treatment of the physical and psychological sequelae of menopause, as a precursor for the intracrine synthesis of estrogens and/or androgens in gonadal steroid target tissues. Because DHEA itself has only weak hormonal activity, it appears potentially capable of providing replacement therapy targeted to the organs that contain the enzyme systems necessary for conversion of DHEA to more biologically active steroids, without the side effects associated with systemic androgen or estrogen replacement (2, 3).

Falling levels of gonadal steroids have been implicated as a contributory factor to the decline in cognitive function that occurs late in life. In aging men and women, circulating levels of gonadal steroids have been positively associated with cognitive performance (4, 5). In laboratory animals, androgens and estrogens both significantly enhance cognitive performance (6, 7). This response has been associated with the effects of these steroids on dendritic structure and synaptic density in the hippocampus, a region of the brain vital for the processing of mnemonic information (8, 9). The present study was designed to determine whether DHEA induces similar hippocampal responses and, if so, whether these effects are primarily mediated via androgen action or intermediate estrogen biosynthesis. In particular, we were interested in determining whether DHEA treatment, at a dose below that required to elicit systemic estrogenic responses, might significantly increase hippocampal synaptic density.

Materials and Methods

Animals
Female Sprague Dawley rats (240–270 g; Charles River Laboratories, Wilmington, MA) housed in individual cages were maintained on a 12-h light, 12-h dark cycle and provided with unlimited access to water and rat chow for the duration of the experiment. Animal protocols were in compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committee of Yale University. Surgical interventions and perfusions were carried out under deep anesthesia, using a ketamine-based anesthetic (25 mg/ml ketamine, 1.2 mg/ml xylazine, and 0.03 mg/ml acepromazine in saline; 3 ml/kg im).

Surgery and hormonal manipulations
Rats were ovariectomized (OVX) under anesthesia via small dorsal flank incisions. One week later, rats received DHEA (Sigma Chemical Co., St. Louis, MO) given in the form of two sc injections (1 mg/d, in sesame oil) separated by 24 h. Control animals were OVX for the same length of time and then treated with the oil injection vehicle alone. An additional group of rats received the same DHEA treatment (1 mg/d for 2 d) after injection of the aromatase inhibitor letrozole (Novartis AG, Basel, Switzerland; 1 mg/d dissolved in 200 µl 2.5% carboxymethylcellulose) (10). The letrozole injections preceded the DHEA by 1 h to allow time for complete aromatase blockade before administration of the androgen. One final group of animals, used as a positive control in the study of DHEA uterotrophic activity (see below), was injected with estradiol benzoate (EB; 10 µg/d for 2 d).

Tissue processing
Forty-eight hours after the second steroid or sesame oil vehicle injection, rats were anesthetized and perfused transcardially with 50 ml heparinized saline, followed by a fixative containing 4% paraformaldehyde and 0.1% glutaraldehyde in PBS. The brains and uteri were removed and postfixed overnight in the same fixative, without glutaraldehyde. The hippocampi were dissected out, and vibratome sections (100 µm) were cut perpendicular to the longitudinal axis of the hippocampus. The sections were osmicated (1% osmium tetroxide in PBS) for 40 min, dehydrated in ethanol (the 70% ethanol contained 1% uranyl acetate) for 40 min, and flat embedded in Araldite. Portions of each uterus were cryoprotected by equilibration with 30% sucrose at 4 C and snap frozen. Cryostat cross-sections (20 µm) were cut, mounted on gelatin-coated slides, stained with solution II of the Diff-Quik stain set (Dade Behring Inc., Newark, DE), dehydrated in ethanol, cleared in xylenes, and coverslipped with DPX (distyrene in xylene).

To evaluate the uterotrophic effects of the treatments, additional rats in each treatment group were killed without perfusion 48 h after the second steroid or sesame oil vehicle injection. Uteri were removed, drained of intraluminal fluid, cleaned of adhering fat and connective tissue, and weighed immediately.

Synapse counts
Spine synapse density was calculated according to our standard protocol using unbiased stereological methods (11). Briefly, to assess possible changes in the volume of the tissue, a correction factor was calculated assuming that the hormonal treatments did not alter the total number of pyramidal cells. Thus, in all hippocampi, six to seven disector pairs (pairs of adjacent 2-µm toluidine-blue-stained semithin sections mounted on slides) were analyzed using the technique of Braendgaard and Gundersen (12). The pyramidal cell density value (D) was calculated using a formula D = N/sT, where N is the mean dissector score across all sampling windows, T is the thickness of the sections (2 µm), and s stands for the length of the window. Based on these values, a dimensionless volume correction factor kv was introduced: kv = D/D1, where D1 is the main density across the groups of hippocampi.

Thereafter, pairs of consecutive serial ultrathin sections (reference and look-up) were cut from the vibratome sections taken from all parts of the hippocampus along its longitudinal axis. The section pairs were collected on Formvar-coated single-slot grids. Subsequently, digitized images were taken at a magnification of x11,000 in a Tecnai 12 transmission electron microscope furnished with an AMT Advantage 4.00 HR/HR-B CCD camera system from an area located between the upper and middle third of the CA1 stratum radiatum (300–500 µm from the pyramidal cell layer). Identical regions in reference and look-up sections were identified using landmarks such as myelinated fibers, large dendrites, or blood vessels that did not change significantly between neighboring sections due to their size. Areas occupied by potentially interfering structures such as blood vessels, large dendrites, or glial cells were subtracted from the measured areas using the NIH Scion image-processing software.

To obtain a comparable measure of synaptic numbers, unbiased for possible changes in synaptic size, the disector technique was used (13). The digitized electron micrographs were printed out using a Brother HL-1450 laser printer. Before data analysis, the printed pictures were coded, and the code was not broken until the analysis was completed. Only those spine synapses were counted that were present in the reference section but not in the look-up section. To increase the efficiency of spine synapse counting, the analysis was performed treating each reference section as a look-up section and vice versa (14).

The density of spine synapses of pyramidal cell dendrites was calculated with the help of a reference grid superimposed on the electron microscopic prints. The disector volume (volume of reference) was the unit area of the reference grid multiplied by the distance between the upper faces of the reference and look-up sections (12). Section thickness (average 0.075 µm) was determined using the electron scattering technique. The measured synaptic density values were divided by the volume correction factor kv. This correction provided a synaptic density estimate normalized with respect to the density of pyramidal cells and also accounted for possible changes in hippocampal volume.

At least five neuropil fields (each 80 µm2) were photographed on each electron microscopic grid. With at least three grids (containing a minimum of two pairs of consecutive, serial ultrathin sections) prepared from each vibratome section (cut from the three portions of the hippocampus along its longitudinal axis), each animal provided at least 3 x 3 x 5 x 2 = 90 neuropil fields for evaluation, corresponding to a total section area of 7200 µm2 (a total neuropil volume of 540 µm3) per animal. Individual mean synapse densities for each animal were used to calculate values for overall synapse density in each experimental group. Results were analyzed by means of an initial two-way ANOVA, followed by the Scheffé test for comparison of individual group means.

Results

Hormonal manipulation-induced changes in CA1 pyramidal spine synapse density
Pyramidal cell spine synapse density was increased significantly in the CA1 stratum radiatum of the DHEA-treated animals (Fig. 1Go). DHEA treatment elevated spine synapse density by 58% from 0.60 ± 0.02 synapse/µm3 in OVX rats to 0.94 ± 0.02 synapse/µm3 in DHEA animals. The aromatase inhibitor letrozole completely abolished the effect of DHEA on synapse numbers. Spine synapse density measured in the CA1 region of letrozole + DHEA-treated animals (0.62 ± 0.02 synapse/µm3) was statistically indistinguishable from that in OVX rats.



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  		FIG. 1. Effect of DHEA treatment in the presence or absence of the aromatase inhibitor letrozole on CA1 spine synapse density in OVX female rats. Rats were given two daily injections of DHEA (1 mg/d sc; n = 4) with or without letrozole (LET) (1 mg/d; n = 3). OVX controls (n = 3) received the injection vehicle alone. Spine synapse densities in the CA1 area of the hippocampus were determined at 48 h after the second daily injection and are presented as the mean number of synapses per cubic micron ± SEM. *, Significantly different from OVX controls (P < 0.01, Scheffé test).

 
Peripheral effects of hormonal manipulations
The effects on the uterus of DHEA treatment with and without letrozole are shown in Fig. 2Go. As expected, uterine weight increased more than 2-fold after EB treatment (Fig. 2AGo). By contrast, uterine weights in the DHEA-treated rats remained comparable to that in the vehicle-injected controls, regardless of whether the animals had been pretreated with letrozole. Statistical analysis indicated that the effects of EB were highly significant, but there were no significant differences between the vehicle- and DHEA-treated females (one-way ANOVA F = 36.0; df = 3, 8; P < 0.0001; Scheffé test EB > oil = DHEA = letrozole + DHEA; P < 0.001).



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  		FIG. 2. Effects of DHEA and letrozole on the uteri. A, Uterine wet weights (means ± SEM; n = 3 for all treatments). *, Significantly different from OVX controls (P < 0.01, Scheffé test). Results that are not significantly different from one another are bracketed together. B–E, Cryostat cross-sections through the uterus, stained with Diff-Quik, are shown for each treatment group: B, OVX; C, DHEA treated; D, letrozole + DHEA; E, EB. DHEA treatment, with or without letrozole, had no detectable uterotrophic effect. Bar, 1 mm.

 
Representative micrographs depicting the histology of the uteri are shown in the lower panels of Fig. 2Go. In all DHEA-treated rats, whether or not they were pretreated with letrozole, the uterus remained completely atrophic, comparable in appearance and diameter to the uteri from control vehicle-injected OVX rats. Light microscopic analysis of uterine cross-sections revealed no evidence of endometrial or myometrial growth after either DHEA (Fig. 2CGo) or letrozole + DHEA treatments (Fig. 2DGo). This contrasts strikingly with the uteri of EB-treated animals, in which the diameter of the uterine lumen as well as the volume of endometrial and myometrial tissue was increased dramatically (Fig. 2EGo) compared with OVX vehicle-injected animals (Fig. 2BGo).

Discussion

These results demonstrate that DHEA treatment induces a dramatic increase in the density of dendritic spine synapses in the CA1 field of the hippocampus in OVX rats. The density of CA1 spine synapses after 2 d of DHEA injections is close to the levels previously reported by us after treatment of OVX rats for 2 d with 10 µg/d EB (15). Unlike systemic estrogen treatment, however, DHEA, at least at the doses used here, does not induce a concomitant uterotrophic response.

DHEA has been reported to have a wide variety of potentially beneficial biological effects, including effects on the immune system, growth rates of mammary tumors, and regulation of blood glucose as well as on both mood state and libido (2, 3, 16). These observations, combined with the well documented decline in circulating DHEA levels that occurs during aging, have resulted in widespread use of DHEA as a hormonal supplement (17). DHEA is also synthesized in the brain, albeit to a much more limited extent than in the adrenal glands (18). Studies over the last decade have revealed significant effects of DHEA on neurotransmitter function as well as neuronal development and survival (reviewed in Ref. 19). With few exceptions, however, the mechanisms by which DHEA exerts these effects remain poorly defined.

The rat provides a good model to investigate the effects of systemic DHEA treatment because it has low endogenous circulating levels of this steroid (20). Theoretically, DHEA could affect CA1 spine synapse density in OVX female rats via one or a combination of several potential mechanisms: 1) via androgen agonist activity of either DHEA itself or one of its metabolites (which include testosterone and dihydrotestosterone); 2) through aromatization of DHEA to estrogen; or 3) through conversion of DHEA to estrogenic C-19 metabolites via pathways independent of aromatization. DHEA is extensively converted to androst 5-ene-3ß,17ß-diol (androstenediol) by 17ß-hydroxysteroid dehydrogenase. Androstenediol has estrogen agonist activity (21, 22), circulating in women at nanomolar concentrations (2). Similarly, dihydrotestosterone is converted to 5{alpha}-androstan-3{alpha},17ß-diol (3{alpha}A-diol) as well as its 3ß-isomer (3ßA-diol). Both 3{alpha}A-diol and 3ßA-diol have weak estrogenic activity (21), whereas 3{alpha}A-diol has also been implicated in androgen regulation of GABA-benzodiazepine receptor function (23).

The present data indicate that enhancement of CA1 synapse density after short-term DHEA treatment is dependent on aromatization. Thus, the effects of DHEA were blocked by pretreatment with the powerful and selective nonsteroidal aromatase inhibitor, letrozole. We have reported elsewhere that letrozole injections identical with those used here do not affect CA1 spine synapse density in OVX rats treated with either sesame oil or the nonaromatizable androgen, dihydrotestosterone (24). Thus, the effect of letrozole on DHEA-induced synaptogenesis cannot be ascribed to either nonspecific effects on synapse numbers or interference with androgen receptor-mediated responses. The hypothesis that the synaptic effects of DHEA are mediated via aromatization is consistent with the recent study of Veiga et al. (25), which demonstrated that the neuroprotective effects of DHEA in the male rat hippocampus are also prevented by aromatase blockade. Because, in the present study, the effect of DHEA was not accompanied by any significant uterotrophic effect, it seems likely that conversion of DHEA to estrogen occurred within the brain itself, because systemic estrogen formation would be expected to induce a uterine response. The actual site of DHEA aromatization remains to be determined. Previous work has demonstrated expression of aromatase in the hippocampus (26). However, aromatase activity is considerably higher in other areas of the brain, including the hypothalamus, preoptic area, and amygdala, than in any region of the hippocampus (27). This raises the possibility that DHEA-induced enhancement of CA1 spine synapse density could be mediated indirectly via actions on aromatase-rich regions of the basal forebrain that project to CA1. Consistent with this hypothesis, in OVX rats, estrogen implants into the basal forebrain mimic the effects of systemic estrogen treatment on CA1 synapse density, whereas destruction of the basal forebrain cholinergic neurons abrogates responses to systemic estradiol administration (28).

These results have important implications for both the normal physiological role of DHEA as well as the use of DHEA as a component of hormone replacement regimens. Reduced DHEA biosynthesis represents a substantial component of the profound decline in overall androgen production that occurs in both men and women with advancing age (1, 2). Although the cognitive effects of systemic estrogen and progestin replacement therapy remain controversial, there is a consensus that endogenous gonadal steroids have important effects on the brain, particularly in women at around the time of menopause (4, 5, 29). Given the neuroprotective and trophic properties of DHEA (19), it seems possible that the dramatic decline in circulating DHEA levels that occurs in humans between the ages of 30 and 60 could contribute to the development of age-related neurodegenerative disorders. In addition to its other biological properties, DHEA may provide a mechanism for local delivery of estrogen to aromatase-containing regions of the brain that depend for maintenance of normal structure and function on continued estrogenic stimulation. If so, carefully controlled DHEA treatment, designed to blunt or prevent the normal age-related decline in this steroid, might help to ameliorate the effects of postmenopausal estrogen deprivation on the brain with less risk of breast and endometrial carcinoma than conventional estrogen-based hormone replacement therapy (2, 30).

Acknowledgments

We thank the excellent technical assistance of Erzsebet Borok. We are indebted to Dr. Richard Hochberg for his help with the design and conduct of these studies.

Footnotes

This work was supported by NIH Grants MH60858 and NS42644.

Abbreviations: DHEA, Dehydroepiandrosterone; EB, estradiol benzoate; OVX, ovariectomized.

Received September 19, 2003.

Accepted for publication November 17, 2003.

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