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The Journal of Neuroscience, March 1, 2003, 23(5):1588
BRIEF COMMUNICATION
Gonadal Hormones Affect Spine Synaptic Density in the CA1
Hippocampal Subfield of Male Rats
Csaba
Leranth1, 2,
Ors
Petnehazy1, and
Neil J.
MacLusky3
Departments of 1 Obstetrics and Gynecology and
2 Neurobiology, Yale University School of Medicine, New
Haven, Connecticut 06520, and 3 Center for Reproductive
Sciences, Columbia University Medical School, New York, New York 10032
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ABSTRACT |
The effects of androgen on the density of spine synapses on
pyramidal neurons in the CA1 area of the hippocampus were studied in
male rats. Gonadectomy (GDNX) had no significant effect on the number
of CA1 pyramidal cells but reduced CA1 spine synapse density by almost
50% (to 0.468 ± 0.018 spine synapses/µm3)
compared with sham-operated controls (0.917 ± 0.06 spine
synapses/µm3). Treatment of GDNX rats with
testosterone propionate (500 µg/d, s.c., 2 d) increased spine
synapse density to levels (1.01 ± 0.026 spine
synapses/µm3) comparable with intact males. A
similar increase in synapse density (1.013 ± 0.05 spine
synapses/µm3) was observed in GDNX animals after
treatment with dihydrotestosterone (DHT) (500 µg/d, s.c., 2 d)
but not after estradiol (10 µg/d, s.c., 2 d; 0.455 ± 0.02 spine synapse/µm3). These data indicate that
testosterone is important for maintenance of normal spine synapse
density in the CA1 region of the male rat hippocampus. The comparable
responses to testosterone and the non-aromatizable androgen DHT,
coupled with the lack of response to estradiol, suggest that
testosterone acts directly on hippocampal androgen receptors rather
than indirectly via local estrogen biosynthesis.
Key words:
testosterone; dihydrotestosterone; estrogen; spine
synapse density; CA1 hippocampal area; unbiased stereological
calculation
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Introduction |
Previous studies have demonstrated
that, during the female reproductive cycle, physiological levels of
gonadal steroids greatly influence the density of pyramidal cell
dendritic spines and spine synapses in the CA1 subfield of the
hippocampus (Gould et al., 1990 ; Woolley et al., 1990; Woolley and
McEwen, 1992; Leranth et al., 2000, 2002). In ovariectomized (OVX)
rats, intact subcortical connections to the hippocampus are required
for estrogen-induced increases in spine synapse density (Leranth et
al., 2000), whereas local administration of estradiol (E) into the
supramammillary area mimics the effects of systemic E administration
(Leranth and Shanabrough, 2001), suggesting that the effects of E on
CA1 pyramidal cells are at least partly indirect.
The male rat hippocampus is rich in androgen receptor-expressing
cells (Simerly et al., 1990; Brown et al., 1995), indicating that it is
a target for testosterone (T) action. In the CA1 area, the androgen
receptors appear to be primarily located in pyramidal neurons (Clancy
et al., 1992; Kerr et al., 1995). The rat hippocampus also contains low
levels of aromatase (MacLusky et al., 1994), the enzyme converting T to
E. Thus, effects of circulating T could be mediated either via actions
of the steroid on androgen receptors or conversion to E. Morphological
studies suggests that androgens and estrogens both modulate hippocampal
structure in the male. In the CA1 area, spine density peaks at puberty
in male mice, and this increase can be prevented by prepubertal
castration (Meyer et al., 1978). Orchidectomy reduces the
density of CA1 area pyramidal cell spines in male rats, an effect that
is partially reversed by E administration (Lewis et al., 1995). These
previous studies, however, used techniques (light microscopic
examination of Golgi-impregnated material) that do not provide
information about synaptic connectivity.
The hippocampus is sexually differentiated as a result of developmental
androgen exposure in the male (Roof and Havens, 1992; Lewis et al.,
1995; Isgor and Sengelaub, 1998). In females, the E-induced increase in
spine synapse density in OVX rats is associated with augmented CA1
long-term potentiation (LTP) (Cordoba Montoya and Carrer, 1997),
whereas T administration to castrated, adult males has been reported to
have an opposite, negative effect on CA1 LTP (Harley et al., 2000). A
possible interpretation of these findings might be that the effects of
E on the hippocampus of the male are different from those of the
female. Alternatively, it is possible that the effects of T might
involve contributions from both androgen and estrogen receptor-mediated
events, resulting in different morphological consequences after
exposure to T or E.
The aim of this study, therefore, was to determine the effects of T and
E on the density of spine synapses on CA1 area pyramidal cells in
gonadectomized male rats. Our data suggest that, in the male, T has a
dramatic impact on CA1 spine synapse density but that this effect is
mediated primarily via androgen rather than estrogen receptors.
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Materials and Methods |
Animals. Male Sprague Dawley (280-300
gm; Charles River Laboratories, Wilmington, MA)
rats were used in this study. Animals were kept under standard
laboratory conditions, with tap water and regular rat chow available
ad libitum, in a 12 hr light/dark cycle. Experiments
conformed to Yale University and international guidelines on the
ethical use of animals, and experimental protocols were approved by the
Institutional Animal Care and Use Committee of Yale University Medical School.
Surgery and hormonal manipulations. Rats were deeply
anesthetized using a ketamine-xylazine mixture (3 ml/kg, i.m.;
containing 25 mg of ketamine, 1.2 mg of xylazine, and 0.03 mg of
acepromazine in 1 ml of saline) and gonadectomized (GDNX). One week
later, four rats received testosterone propionate (TP), four rats
received dihydrotestosterone (DHT), and four rats received estradiol
benzoate treatment. Treatments consisted of two subcutaneous injections separated by 24 hr of 500 µg of TP, 500 µg of DHT, or 10 µg of E
(in 100 µl of sesame oil), respectively. The control animals (n = 4) were sham operated and received only sesame oil
injections. Rats were kept in individual cages.
Tissue processing. Two days after the second hormone
injection, rats were killed under deep ether anesthesia by transcardial perfusion of heparinized saline, followed by a fixative containing 4%
paraformaldehyde and 1% glutaraldehyde in 0.1 M
phosphate buffer, pH 7.35. Brains were removed and postfixed for 2 hr
in the same fixative. The hippocampi were dissected out, and vibratome
sections (100 µm) were cut perpendicular to the longitudinal axis of
the hippocampus. Sections were postfixed in 1% osmium tetroxide (30 min), dehydrated in ethanol (the 70% ethanol contained 1% uranyl acetate for 30 min), and flat embedded in Araldite.
Synapse counts. The spine synapse density was calculated
according to our standard protocol using unbiased stereological methods (Leranth et al., 2000, 2002; Leranth and Shanabrough, 2001). Briefly, first to assess possible changes in the volume of the tissue, a
correction factor was calculated assuming that the brief hormonal treatments do not alter the total number of pyramidal cells (Rusakov et
al., 1997). 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 Braendgaar and
Gundersen (1986). The pyramidal cell density value
(D) was calculated using the formula
D = N/sT, where
N is the mean disector score across all of the sampling
windows, T is the thickness of the sections (2 µm), and
s stands for the length of the window. On the basis of 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" sections) were cut from the
vibratome sections (representing all areas of the hippocampus along its
longitudinal axis) from an area located between the upper and middle
third of the CA1 stratum radiatum (3-500 µm from the pyramidal cell
layer) and collected on Formvar-coated single-slot grids. Digitized
images were made at a magnification of 11,000× in a Tecnai 12 electron microscope furnished with an AMT Advantage 4.00 HR/HR-B CCD camera system connected to a computer via a PCI-Bus frame grabber board (Advanced Microscopy Techniques, Danvers, MA) with the observer blinded
to the experimental treatment. Areas occupied by potentially interfering structures, such as blood vessels, large dendrites, or
glial cells, were subtracted from the areas measured 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 (Sterio, 1984). Thus, the density
of spine synapses of pyramidal cell dendrites was calculated with the
help of a reference grid superimposed on the EM 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 (Braendgaar and Gundersen, 1986). Only those spine
synapses were counted that were present on the reference section but
not on the look-up section (Fig. 1). To
increase the efficiency of spine synapse counting, the analysis was
performed treating each reference section as a look-up section and vice
versa (Woolley and McEwen, 1992). Section thickness (average of 0.075 µm) was determined by using the electron scattering technique (Small,
1968). 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.
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Figure 1.
Electron micrographs demonstrate identical areas
on two consecutive, serial sections taken from the stratum radiatum of
the CA1 subfield. a shows the reference section and
b the look-up section. Only those spine synapses were
counted that were seen just in one section. Long arrows
point at the same spine, which forms synaptic contact only in
b. Spine synapses that are in postsynaptic position in
both sections (small arrows) and axo-dendritic synapses
were not counted. D, Dendrite. Scale bar, 1 µm.
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Statistical analysis. At least five neuropil fields were
photographed on each electron microscopic grid. With at least eight grids from each vibratome section (containing a minimum of two pairs of
consecutive, serial ultrathin sections), each animal provided a minimum
of 5 × 8 × 2 = 80 or more neuropil fields. The means
and SEs were calculated. Means were compared using pairwise t tests (two-tailed probabilities) among groups, as well as
using the noncentral F statistic to test the difference in
the ratios of means between groups. A level of confidence of
p < 0.05 in two-tailed tests was adopted.
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Results |
No significant differences were observed between the density
values of CA1 pyramidal cells of rats that were GDNX and received different hormone treatments and control animals (control, 1780 ± 193 cells/mm2; TP plus GDNX,
1716 ± 168 cells/mm2; DHT plus GDNX,
1702 ± 185 cells/mm2; E plus GDNX,
1750 ± 175 cells/mm2).
In the electron microscope, no obvious qualitative differences could be
observed by comparing the ultrastructure of the CA1 stratum radiatum of
control rats and animals that received different hormonal treatments.
In contrast, the results of the unbiased statistical analyses provided
evidence of different effects of the various hormone treatments on the
density of spine synapses in this region (Fig.
2). The highest density of CA1 area
pyramidal cell spine synapses was calculated in the gonadectomized and
TP- or DHT-treated rats. A slightly, but not significantly, lower synaptic density was observed in the sham-gonadectomized control group.
Significantly lower (~50%) spine synapse densities were observed in
the GDNX- and GDNX plus estrogen-treated rats (Fig. 2).
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Figure 2.
Bar graph shows the result of the unbiased
stereological calculation of spine synapse density in the stratum
radiatum of the CA1 subfield of control, gonadectomized
(GDX), gonadectomized plus testosterone-treated
(GDX+T), gonadectomized plus
dihydrotesterone-treated (GDX+DHT), and
gonadectomized plus estrogen-treated (GDX+E2) male rats.
There is no significant difference between the density values of spine
synapses between the Control, GDX+T, and
GDX+DHT animals. However, the spine synapse density of
the GDX and GDX+E2 rats is significantly
(p < 0.001) lower (48%) than that of
control animals.
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Discussion |
These observations demonstrate that, in adult male rats, the
integrity of CA1 area pyramidal cell spine synapses depends on the
presence of circulating testosterone. GDNX dramatically reduces the
number of spine synapses, a response that is reversed by treatment with
either T or the non-aromatizable androgen DHT. In contrast, E
administration has no significant effect on the spine CA1 synapse density in GDNX animals.
These data indicate a striking sexual dimorphism in the response
mechanisms that maintain normal hippocampal CA1 structure. In the
female, estrogen is a potent modulator of CA1 spine synapse density
(Gould et al., 1990; Woolley et al., 1990; Woolley and McEwen,
1992; Leranth et al., 2000, 2002). In the male, however, the present
data indicate that the dramatic loss of hippocampal CA1 spine synapse
density after GDNX is not significantly affected by short-term E
treatment. In contrast, treatment with T or DHT completely reverses the
post-orchidectomy decline in hippocampal spine synapse numbers. The
lack of effect of estrogen administration and the comparable responses
observed with T and DHT strongly suggest that the effect of T is
mediated via androgen receptors rather than by conversion of the
androgen to estrogen. Different doses of E and the two androgens were
used to reflect the fact that androgens normally circulate in the
bloodstream at much higher levels than E, whereas only a small
proportion of circulating T is normally aromatized and concentrated in
the rat brain (Lieberburg and McEwen, 1977). The comparable response to
T and DHT is consistent with the view that relatively little conversion
of T to E occurs in the adult rat hippocampus (Lieberburg and McEwen,
1977; MacLusky et al., 1994). The apparent lack of response to systemic
E administration is somewhat unexpected, in view of previous data
indicating effects of E treatment on dendritic structure in males,
particularly because the doses of E used in this previous study (Lewis
et al., 1995) were identical to those used here. In this previous
study, however, the effects of E treatment on dendritic spine density,
although statistically significant, were quantitatively much smaller
than the effect of GDNX. Thus, spine density on the primary apical dendrites of CA1 pyramidal neurons was reduced by almost 50% after GDNX (Lewis et al., 1995), a response consistent with the almost 50%
decrease in the number of spine synapses observed in the present study.
In contrast, E treatment induced only an ~10% increase in dendritic
spine density (Lewis et al., 1995) and no significant change in the
number of spine synapses per cubic micrometer (Fig. 2).
Although the difference between the effects of DHT and E clearly
suggests that estrogen receptors do not mediate the synaptic response
to T, this does not prove that T acts solely via the hippocampal
intranuclear androgen receptor system. There may also be contributions
from direct modulation of neurotransmitter receptor function. For
example, T and DHT are both converted to 5 -androstan 3 17
diol, which has been reported to have significant modulatory effects on
GABAA receptors. This route of metabolism has
been implicated in the behavioral effects of circulating androgens (Bitran et al., 1996; Frye and Reed, 1998; Frye et al., 2001).
Previous studies have demonstrated that androgens have powerful
neuroprotective and homeostatic effects in the hippocampus (Sakata et
al., 2000; Azcoitia et al., 2001; Pike, 2001; Shors et al., 2001). In
several species, the hippocampus is sexually differentiated, at least
in part because of androgen action in the male (Meyer et al.,
1978; Lewis et al., 1995; Tabibnia et al., 1999). A significant
positive effect of testosterone on hippocampal volume has been reported
in meadow voles (Galea et al., 1999). Hippocampal CA1 spine density has
been reported to be higher in females at proestrus than in males and to
respond to stress in different directions in males and cycling females
(Shors et al., 2001). A developmental component to sex differences in
hippocampal structure is also suggested by studies demonstrating
positive effects of perinatal androgen exposure in rats on CA1, CA3,
and dentate gyrus cell densities (Roof and Havens, 1992; Isgor and Sengelaub, 1998). These long-term, differentiating effects of early
androgen differ, however, from the more rapid, activational effects
reported here: GDNX results within 10 d in an ~50% loss of CA1
spine synapse density, an effect that is completely reversed within
3 d of instituting T or DHT replacement therapy (Fig. 2).
Numerous reports in the literature suggest that T has effects on
neuroendocrine, neurophysiological, and behavioral responses involving
the hippocampus. Patchev and Almeida (1996) have reported that
hippocampal mineralocorticoid receptor (MR) and glucocorticoid receptor
(GR) mRNA expression is regulated by gonadal steroids in
adrenalectomized rats, in a sex-specific manner. Thus, hippocampal MR
expression was significantly downregulated by E only in females, whereas E-induced changes in GR expression were observed only in males.
In contrast, DHT significantly downregulated hippocampal MR expression
in both sexes (Patchev and Almeida, 1996). The effects of androgens and
E on GR and MR regulation may contribute to the reported effects of
these steroids on the neuroendocrine control of ACTH secretion. GDNX
enhances the ACTH response to stress (Handa et al., 1994).
Administration of E further augments stress-induced ACTH secretion in
GDNX animals, whereas T or DHT return post-stress ACTH to levels
comparable with those observed in intact rats (Handa et al., 1994).
Sexual dimorphisms in the electrophysiological properties of the
hippocampus also involve acute, activational effects of gonadal
steroids (Foy et al., 1984). Smith et al. (2002) have reported recently
that, after stimulation via the Schaeffer collaterals, hippocampal
slices from intact male rats exhibit larger EPSP amplitudes
recorded in CA1 than slices from either females or GDNX males. In
vitro application of T significantly increased EPSP amplitudes in
both sexes (Smith et al., 2002). The effects of androgen on hippocampal
LTP are mixed and appear to depend on the experimental model. Using
urethane-anesthetized male rats stimulated via the Schaeffer
collaterals, Harley et al. (2000) reported that orchidectomized male
rats show a significantly greater magnitude and duration of
potentiation than rats replaced with T or DHT. In male mice, in
contrast, Sakata et al. (2000) reported that, whereas LTP in CA1
pyramidal neurons evoked by high-frequency stimulation via commissural
afferents is unaffected by gonadal status, LTP evoked by primed burst
stimulation is attenuated by castration and restored to control levels
by testosterone treatment. In this respect, the effects of T
superficially resemble those of E, which has also been shown to
increase hippocampal excitability (Wong and Moss, 1992; Woolley et al.,
1997) and potentiate LTP (Cordoba Montoya and Carrer, 1997) but induce
increases in CA1 spine density (Woolley and McEwen, 1992; Woolley et
al., 1997). Thus, although the responses to T and E appear to be
initiated via different receptor systems, the end result for both
steroids may reflect intermediary mechanisms involving increases in
hippocampal neuronal activity.
Behavioral studies indicate a potential role for T in maintenance of
normal cognitive function in both man and animals. In dogs,
orchidectomy has been associated with more rapid cognitive decline in
aging (Hart, 2001), although in mice, age-related decrements in
cognitive function have been associated with decreased levels of
circulating T (Flood et al., 1995). In man, circulating T
concentrations tend to be depressed in men with Alzheimer's disease
(Hogervorst et al., 2001), although in normal older men higher
bioavailable T levels are associated with better cognitive performance
(Barrett-Connor et al., 1999; Yaffe et al., 2002). Consistent with
these observations, short-term T treatment has been reported to improve
verbal and visuospatial memory in healthy older men (Janowsky et al.,
2000; Cherrier et al., 2001). Although the mechanisms underlying these observations remain to be established, in females the trophic effects
of estrogen on hippocampal structure have been implicated as a
potential contributory factor to the enhancement of cognitive performance observed after estrogen replacement (Cordoba Montoya and
Carrer, 1997; Luine, 1997). T-mediated remodeling of hippocampal structure might play a comparable role in the behavioral effects of
this hormone.
In conclusion, these data indicate that T is required for maintenance
of normal spine synapse density in the CA1 region of the male rat
hippocampus. The fact that the effects of T are not reproduced by
administration of E, although they are replicated by administration of
the non-aromatizable androgen DHT, strongly suggests that the response
to T is mediated via androgen-specific receptor systems rather than by
local conversion of the androgen to estrogen. Androgen-induced changes
in hippocampal structure may contribute to the effects of T on
hippocampally mediated behaviors and the regulation of the
hypothalamic-pituitary-adrenal axis.
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FOOTNOTES |
Received Oct. 9, 2002; revised Dec. 18, 2002; accepted Dec. 18, 2002.
This work was supported by National Institutes of Health Grants MH60858
and NS42644 (C.L.).
Correspondence should be addressed to Dr. Csaba Leranth, Department of
Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar Street, Farnam Memorial Building 313, New Haven, CT
06520-8063. E-mail: csaba.leranth{at}yale.edu.
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TOP
ABSTRACT
Introduction
