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Volume 17, Number 5,
Issue of March 1, 1997
pp. 1848-1859
Copyright ©1997 Society for Neuroscience
Estradiol Increases the Sensitivity of Hippocampal CA1 Pyramidal
Cells to NMDA Receptor-Mediated Synaptic Input: Correlation with
Dendritic Spine Density
Catherine S. Woolley1,
Nancy G. Weiland2,
Bruce S. McEwen2, and
Philip A. Schwartzkroin1
1 Department of Neurological Surgery, University of
Washington, Seattle, Washington 98195, and 2 Laboratory of
Neuroendocrinology, The Rockefeller University, New York, New York
10021
ABSTRACT
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- DISCUSSION
- FOOTNOTES
- REFERENCES
ABSTRACT 
Previous studies have shown that estradiol induces new dendritic
spines and synapses on hippocampal CA1 pyramidal cells. We have
assessed the consequences of estradiol-induced dendritic spines on CA1
pyramidal cell intrinsic and synaptic electrophysiological properties.
Hippocampal slices were prepared from ovariectomized rats treated with
either estradiol or oil vehicle. CA1 pyramidal cells were recorded and
injected with biocytin to visualize spines. The association of
dendritic spine density and electrophysiological parameters for each
cell was then tested using linear regression analysis. We found a
negative relationship between spine density and input resistance;
however, no other intrinsic property measured was significantly
associated with dendritic spine density. Glutamate receptor
autoradiography demonstrated an estradiol-induced increase in binding
to NMDA, but not AMPA, receptors. We then used input/output (I/O)
curves (EPSP slope vs stimulus intensity) to determine whether the
sensitivity of CA1 pyramidal cells to synaptic input is correlated with
dendritic spine density. Consistent with the lack of an estradiol effect on AMPA receptor binding, we observed no relationship between the slope of an I/O curve generated under standard recording
conditions, in which the AMPA receptor dominates the EPSP, and spine
density. However, recording the pharmacologically isolated NMDA
receptor-mediated component of the EPSP revealed a significant
correlation between I/O slope and spine density. These results indicate
that, in parallel with estradiol-induced increases in spine/synapse
density and NMDA receptor binding, estradiol treatment increases
sensitivity of CA1 pyramidal cells to NMDA receptor-mediated synaptic
input; further, sensitivity to NMDA receptor-mediated synaptic input is
well correlated with dendritic spine density.
Key words:
estradiol;
dendritic spines;
hippocampal slice;
CA1
pyramidal cells;
biocytin;
autoradiography;
NMDA receptor
INTRODUCTION
Since the initial anatomical description of
dendritic spines by Ramon y Cajal in the late 1800s, many investigators
have speculated about dendritic spine function. Spines have been
proposed to play primarily connective, electrical, and/or biochemical
roles in neuronal physiology (for review, see Koch and Zador, 1992
;
Horner, 1993; Harris and Kater, 1994). Recent efforts to understand
dendritic spine function based on imaging of dye-labeled spiny
dendrites have yielded valuable information, particularly with regard
to spines' potential for Ca2+ compartmentalization
(Guthrie et al., 1991; Muller et al., 1991). Such findings have been
incorporated into proposals for dendritic spine function in synaptic
integration (see, for example, Yuste and Denk, 1995) and
neuroprotection (Harris and Kater, 1994; Segal, 1995). An additional
approach to exploring dendritic spine function, which has not been used
to date, is to assess the functional consequences of adding dendritic
spines to the dendrites of spiny neurons.
Hippocampal CA1 pyramidal cells are an ideal population of
neurons in which to implement this approach. First, these cells have
been studied extensively producing a wealth of information regarding
their basic properties. Second, in the female rat, the number of spines
on the dendrites of CA1 pyramidal cells can be manipulated by altering
circulating levels of the ovarian steroid hormone estradiol (Gould et
al., 1990; Woolley and McEwen, 1993). The addition of new spines has
been quantified as an estradiol-induced increase in the density of
spines (number of spines/unit length) on the dendrites of both the
apical and the basal trees of CA1 pyramidal cells. This increase in
spine density reflects an increase in spine number per se, because no
concomitant change in dendritic length or branching pattern is observed
(Woolley and McEwen, 1994). Importantly, increased density of dendritic
spines is paralleled by increased density of axospinous (but not
axodendritic) synapses, indicating that new spines form synaptic
contacts (Woolley and McEwen, 1992).
Estradiol-induced changes in dendritic spine and synapse density are
paralleled by changes in hippocampal physiology that suggest that
increased dendritic spine and synapse density result in increased
excitability. With a time course very similar to spine and synapse
changes, estradiol treatment facilitates acquisition of kindled
seizures in the hippocampus (Buterbaugh and Hudson, 1991), increases
severity of kainic acid-induced seizures (Nicoletti et al., 1985), and
decreases hippocampal seizure threshold (Terasawa and Timiras, 1968).
During the estrous cycle, in which spine and synapse density fluctuate
naturally with changing hormone levels (Woolley et al., 1990), the
threshold for hippocampal seizure activity decreases (Terasawa and
Timiras, 1968) and long-term potentiation (LTP) is enhanced (Warren et
al., 1995) as estradiol levels increase.
To address the relationship between estradiol-induced differences
in hippocampal physiology and differential dendritic spine density on
hippocampal CA1 pyramidal cells, we have recorded CA1 pyramidal cells
in in vitro hippocampal slices from ovariectomized control
and estradiol-treated animals, labeled the cells with biocytin, and
made direct correlations between the electrophysiological (intrinsic
and synaptic) properties and dendritic spine density on each cell.
These experiments provide information regarding both basic questions of
dendritic spine function and the mechanism by which estradiol affects
hippocampal physiology.
MATERIALS AND METHODS
Animal surgery and hormone treatments. Adult female
Sprague Dawley rats were housed on a 12 hr light/dark cycle with
unlimited access to food and water. These animals were left gonadally
intact (intact), ovariectomized and treated with estradiol benzoate
(OVX+E), or ovariectomized and treated with sesame oil vehicle (OVX+O). The hormone treatment regimen that was used in these experiments has
been shown previously to result in differences in CA1 pyramidal cell
dendritic spine (Gould et al., 1990) and synapse (Woolley and McEwen,
1992) density. Six days before electrophysiological analysis, animals
were ovariectomized under Metofane anesthesia using aseptic surgical
procedure. After surgery, animals were housed individually. On days 3 and 4 after surgery, OVX+E animals were injected (s.c.) with 10 µg of
17
-estradiol benzoate in 100 µl of sesame oil vehicle; OVX+O
animals received oil vehicle at each injection time. Forty-eight hours
after the second estradiol or vehicle injection, animals were killed by
decapitation and hippocampal slices were prepared from their brains.
Gonadally intact animals were killed at random stages of the estrous
cycle.
In a separate experiment, animals were similarly prepared for glutamate
receptor autoradiography. This experiment was originally done in
conjunction with analysis of dendritic spine density in which we were
interested in determining the effects of progesterone in addition to
estradiol. As a result, a group of animals that were treated with both
estradiol and progesterone was included. Data from the estradiol plus
progesterone (OVX+EP) animals are included here because the animals
were all part of the same experiment; however, for the purposes of
comparison with electrophysiological data, the OVX+O and OVX+E groups
are the most relevant. For this experiment, adult female rats were
ovariectomized 6 d before killing and were divided into three
treatment groups of nine animals each. OVX+E and OVX+O animals were
treated as described above; OVX+EP animals were treated with estradiol
as above, and then 5 hr before killing they received a single injection
(s.c.) of 500 µg of progesterone in 100 µl of sesame oil. All
animals were killed by decapitation 48 hr after the second estradiol
benzoate or sesame oil injection, and their brains were rapidly removed
and frozen on dry ice and stored at 
70°C until sectioning.
Preparation of hippocampal slices. After decapitation,
brains were quickly removed, cooled briefly with ice-cold, oxygenated (95% O2/5% CO2) sucrose artificial CSF
(sACSF; in mM: 220 sucrose, 3 KCl, 1.25 NaH2PO4, 2 MgSO4, 26 NaCO3, 2 CaCl2, 10 dextrose) and blocked to
contain the dorsal hippocampus. Using a Vibroslicer, 400-µm-thick
slices transverse to the long axis of the hippocampus were cut into a
bath of oxygenated sACSF at 4°C. Sections were then transferred to a
holding chamber, where they remained submerged in oxygenated artificial
CSF (ACSF; in mM: 124 NaCl, 5 KCl, 1.25 NaH2PO4, 2 MgSO4, 26 NaCO3, 2 CaCl2, 10 dextrose) at room
temperature until used for recording.
Slices were allowed to recover at least 30 min after cutting before
they were transferred to a standard interface recording chamber. In the
chamber, slices rested on a nylon mesh over a well that was perfused
with oxygenated ACSF at ~1 ml/min; warmed, humidified air was
circulated above the slice. Temperature was maintained at 34.5°C.
Slices remained undisturbed in the chamber 30 min before recording.
Intracellular recording. Recording electrodes made from
borosilicate glass were pulled using a horizontal puller (Sutter
Instruments) and filled with 2% biocytin dissolved in 1 M
potassium acetate (100-200 M
). Intracellular potentials were
recorded using an Axoclamp 2A amplifier (Axon Instruments, Foster City,
CA). Bridge balance was continuously monitored on an oscilloscope.
Neurons impaled within the CA1 pyramidal cell layer were tentatively
identified as CA1 pyramidal cells on the basis of their response to
direct current injection (Schwartzkroin, 1975); the identity of these cells was confirmed after visualization of injected biocytin. Neurons
were included only if they had a resting potential of at least 55 mV,
overshooting action potentials, and input resistance of at least 25 M. Cell activity and response to stimulation were processed on-line
and stored on videotape using a PCM device (Neuro-Data Instruments).
Data were acquired and analyzed using pClamp software (Axon
Instruments). Biocytin was iontophoretically injected with 300 msec,
0.5-1.0 nA hyperpolarizing current pulses delivered every 600 msec for
10-20 min. Slices remained in the recording chamber for 30 min after
biocytin injection.
In experiments involving synaptic activation of CA1 pyramidal cells, a
bipolar metal stimulating electrode was placed on the surface of the
slice in the proximal stratum (st.) radiatum for Schaffer collateral
stimulation. Stimuli (100 msec duration) were delivered at 0.1 Hz.
In some experiments, 2 mM kynurenic acid was added to the
recording medium to block glutamate receptors nonspecifically. In other
experiments, NMDA receptor-mediated EPSPs were pharmacologically isolated from the composite EPSP using the following modifications of
recording conditions: (1) Mg2+ in the recording medium was
reduced to 0.6 mM; (2) 30 µM
6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) to block non-NMDA glutamate
receptors and 30 µM bicuculline to block
-amino-butyric acid A (GABAA) receptors were added to the recording medium; (3) 200 mM QX-314 was included in the
recording electrode to block Na+ action potentials; (4)
EPSPs were recorded with the cell depolarized to approximately 40
mV.
Extracellular recording. Extracellular recordings were made
to verify linearity in the relationship between the intensity of a
stimulus delivered to the Schaffer collateral pathway and the amplitude
of the presynaptic fiber volley recorded in the CA1 st. radiatum.
Recording electrodes made from borosilicate glass pulled using a
horizontal puller (Sutter Instruments) were filled with 2 M NaCl (5-15 M). Electrodes were placed in the CA1
st. radiatum to record the dendritic EPSP. A bipolar metal stimulating
electrode was placed on the surface of the slice in the proximal CA1
st. radiatum for Schaffer collateral stimulation. Extracellular field
potentials were recorded using an Axoclamp 2A amplifier (Axon
Instruments), processed on-line, and stored on videotape using a PCM
device (Neuro-Data Instruments). Data were acquired and analyzed using
pClamp software (Axon Instruments).
Tissue processing for visualization of biocytin.
Electrophysiological characterization of CA1 pyramidal cells was
carried out before biocytin injection. After biocytin injection, slices were removed from the recording chamber and fixed overnight between two
pieces of filter paper in 4% paraformaldehyde in 0.1 M
phosphate buffer at pH 7.4 (PB) at 4°C. Slices were then rinsed in PB
and cryoprotected in 10% sucrose in PB for 30 min followed by 30% sucrose in PB overnight. Each slice was then resectioned (60 µm) on a
freezing microtome. Tissue sections were processed to visualize biocytin-filled cells as follows. Sections were first rinsed in 0.1 M Tris buffer at pH 7.4 (TB), treated with 0.5-1.0%
H2O2 to suppress endogenous peroxidases,
incubated in 2% bovine serum albumin in 0.25% DMSO in 0.05 M Tris-buffered saline at pH 7.4 (TBS) to block nonspecific
staining and permeabilize membranes. Sections were then rinsed in 0.1 M TBS and incubated in avidin-biotinylated horseradish
peroxidase (Elite ABC kit, Vector Laboratories, Burlingame, CA),
diluted 1:500 in the blocking solution for 48 hr at 4°C. After
incubation, sections were rinsed in 0.1 M TBS followed by 0.1 M TB, preincubated in 0.025% diaminobenzidine (DAB)
and 0.005% NiNH4SO4 for 15 min in the dark.
Sections were then reacted with 0.002% H2O2 in
DAB/NiNH4SO4 for 60-120 min in the dark. After the reaction, sections were rinsed in 0.1 M TB, mounted
onto subbed slides, dehydrated, cleared, coverslipped, and examined for
biocytin-filled cells.
Morphological analysis of biocytin-filled cells.
Tissue-containing CA1 pyramidal cells that were well filled with
biocytin were coded and analyzed (blind to treatment condition) for the density of dendritic spines on lateral branches of the apical dendritic
tree; in some cells, the total two-dimensional dendritic length of the
apical and basal dendritic trees was measured. Multiple cells from each
treatment group were analyzed together, and the code was not broken
until the analysis was complete. CA1 pyramidal cells were determined to
be well filled if a single dark brown-to-black cell body was present
and evenly stained dendrites could be followed into st.
lacunosum/moleculare. Cells with patchy or interrupted dendritic
staining were excluded from analysis. Dendritic spines were not used as
a criterion for the quality of cell filling.
For each cell, dendritic spine density was measured on four to five
dendritic segments in the apical dendritic tree within a range of
150-300 µm from the cell body. To be selected for analysis of spine
density, dendritic segments had to meet two additional requirements:
(1) be relatively thin and of approximately equivalent diameter so as
to minimize the effect of spines hidden either above or below the
dendrite and to equalize these effects between different cells, and (2)
remain in approximately a single plane of focus so that the length of
the dendrite projected in two dimensions would approximate the
three-dimensional dendritic length. Camera lucida drawings (1000×)
were made of each dendritic segment for which spine density was
analyzed. The length of each segment was measured from the camera
lucida drawing (using NIH Image software), the number of dendritic
spines visible along each segment was counted, and spine density was
expressed as number of spines/10 µm dendritic length. For cells in
which total dendritic length was also measured, reconstructions of the
entire dendritic tree were made using a camera lucida (400×), and the
length of dendrites was measured from camera lucida drawings using NIH
Image software. Dendritic length of the apical tree, basal tree, and
combined apical and basal trees was measured for each such cell.
Electrophysiological analysis. Analysis of
electrophysiological data using pClamp software was done only for cells
that were determined to be well filled with biocytin. The following
intrinsic membrane properties were measured: (1) resting membrane
potential was determined upon withdrawal from a recorded cell; (2)
input resistance was determined by linear regression through the
current-voltage relationship. Peak amplitude of the voltage deflection
resulting from hyperpolarizing current pulses ranging from 0.2 to 0.6 nA was measured; (3) time constant was taken to be the time required for the membrane to reach 63% of maximum voltage deflection during a
0.3 nA hyperpolarizing current pulse; (4) mV to threshold; (5) action
potential amplitude; (6) action potential duration was measured at the
base of the spike; (7) spike afterhyperpolarization amplitude; and (8)
spike afterhyperpolarization duration.
The relationship between dendritic spine density and sensitivity to
synaptic input for each cell was determined on the basis of
input/output (I/O) curves in which EPSP initial slope or amplitude was
plotted versus stimulus intensity. A bipolar metal stimulating electrode was placed in the st. radiatum ~1 mm from the recording electrode. In normal recording medium, EPSPs were generated by stimuli
delivered embedded within a 100 msec, 0.5 nA hyperpolarizing current
pulse. Under recording conditions designed to isolate the NMDA
receptor-mediated component of the EPSP (see above), stimuli were
delivered from a membrane potential depolarized to approximately 40
mV. In each case, stimulus intensity was increased in 20 µA
increments from that which produced no detectable postsynaptic response
to a stimulus that produced a maximal postsynaptic response. Ten EPSP
measurements were averaged at each stimulus intensity. EPSP slope and
amplitude were plotted as percent maximum values versus stimulus
intensity. I/O slope was measured by linear regression of the I/O curve
through the range from 25 to 75% maximum EPSP slope or amplitude.
Glutamate receptor autoradiography. Sixteen-micrometer-thick
coronal sections of OVX+O, OVX+E, and OVX+EP brains were cut on a
cryostat and thaw-mounted onto gelatinized slides. These sections were
stored at 70°C until used for autoradiography. Some sections were
stained for Nissl using cresyl violet; these sections were used for
orientation during data analysis. Determination of the NMDA recognition
site was performed according to Weiland (1992a). Slide-mounted sections
were preincubated in 50 mM Tris acetate buffer, pH 7.4, for
45 min at room temperature to remove endogenous ligand. Sections were
then air-dried for 10 min before incubation in 50 mM Tris
acetate buffer containing 200 nM
[3H]glutamate (17.3 Ci/mmol) in either the presence or
the absence of 1 mM NMDA for 30 min at 4°C. After
incubation, the sections were washed four times for 3 sec each in
buffer at 4°C, fixed in acetone with 2.5% gluteraldehyde, and then
dried under a fan.
Determination of the AMPA recognition site was performed according to a
modified version of Dewar et al. (1991). Slide-mounted sections were
preincubated in 50 mM Tris acetate buffer, pH 7.2, at room
temperature for 45 min to remove endogenous ligand. Sections were then
air-dried for 10 min before incubation in 50 mM Tris acetate buffer containing 100 mM KCN and 50 nM
[3H]AMPA (60 Ci/mmol) in either the presence or the
absence of 1 mM glutamate for 45 min at 4°C. After
incubation, the sections were washed three times for 3 sec each in
buffer at 4°C, fixed in acetone with 2.5% gluteraldehyde, and then
dried under a fan.
After binding assays, sections were apposed to either LKB Ultrofilm for
29 d (NMDA-displaceable [3H]glutamate binding) or
LKB Hyperfilm for 2 d ([3H]AMPA binding) with
3H-labeled brain mash standards. Films were developed using
Kodak D-19 developer and fixed with Kodak Rapid-fix.
Quantitative analysis of glutamate receptor binding.
Quantitative analysis of films depicting labeled brain sections and
standards was performed using the DUMAS image analysis program (Drexel
University). This program measures relative optical density and
converts the values to concentration of radioligand (fmol/mg protein)
using a standard curve generated from 3H-labeled brain mash
standards. NMDA receptor binding was taken to be
[3H]glutamate binding that was displaced by NMDA; both
sides of four sections were measured for each of total
[3H]glutamate- and NMDA-displaced binding. AMPA receptor
binding was taken to be [3H]AMPA binding that was
displaced by glutamate; both sides of four sections were measured for
[3H]AMPA binding, and both sides of two sections were
used to determine nonspecific binding. For each ligand, separate
measurements were made for the CA1 st. radiatum and st. oriens.
Statistical analyses. Dendritic spine density on CA1
pyramidal cells from OVX+O and OVX+E animals was compared using an
unpaired, two-tailed Student's t test. The association of
electrophysiological properties and dendritic spine density on CA1
pyramidal cells was determined using simple linear regression analysis
of physiological parameters on spine density. The significance of these
associations was tested using ANOVA. Mean slope of the NMDA
receptor-mediated EPSP I/O curve of cells from OVX+O and OVX+E animals
was compared using an unpaired, two-tailed Student's t
test. For the glutamate receptor binding studies, means were calculated
for each animal and the data were subjected to one-way ANOVA with
Tukey's HSD post hoc comparisons.
RESULTS
For this study, 145 CA1 pyramidal cells were recorded and injected
with biocytin. Of these 145, 69 cells (48%) were determined to be
sufficiently filled with biocytin for analysis of dendritic spine
density. In general, biocytin-filled CA1 pyramidal cells (Fig.
1) were similar in morphology to Golgi-impregnated CA1
pyramidal cells. Initial experiments indicated no obvious differences
in the physiology of CA1 pyramidal cells of different dendritic
morphologies (e.g., nonbifurcated vs bifurcated primary dendrite) or
between cells located in different portions of the CA1 pyramidal cell layer. Thus, all cells in which a particular electrophysiological parameter was measured were grouped together for analysis.
Fig. 1.
Photomicrographs of single sections containing a
representative biocytin-filled CA1 pyramidal cell from an OVX+O
(A) and an OVX+E (B) animal. Camera lucida
tracings of the cell body and complete dendritic tree reconstructed
from all sections containing the same cells from the OVX+O
(C) or OVX+E (D) animal are shown in the
lower panels. Camera lucida tracings were used to determine total dendritic length of each cell; no differences in total dendritic length were observed between treatment groups. Scale bar, 50 µm (applies to all panels).
[View Larger Version of this Image (53K GIF file)]
Dendritic spine density
The density of dendritic spines on biocytin-filled CA1 pyramidal
cells was somewhat higher than previously observed on Golgi-impregnated cells (see, for example, Woolley and McEwen, 1993). The difference in
mean spine density between OVX+O and OVX+E cells was statistically significant but of a slightly lower magnitude than previously reported
for Golgi-impregnated tissue. On biocytin-filled CA1 pyramidal cells,
mean ± SEM spine density was 15.2 ± 1.2 spines/10 µm for
OVX+O compared to 19.4 ± 1.1 spines/10 µm for OVX+E (Figs. 2,
3; T = 4.655,
p < 0.001). Thus, the difference in spine density on
biocytin-filled CA1 pyramidal cells from OVX+O versus OVX+E animals was
22% compared to ~28% previously reported for Golgi-impregnated cells (Woolley and McEwen, 1993). Previous studies based on
Golgi-impregnated tissue have shown that estradiol-induced changes in
the density of dendritic spines in the lateral branches of the apical
dendritic tree are paralleled by similar changes in the dendrites of
the basal tree (Gould et al., 1990; Woolley and McEwen, 1994). In general, changes observed in the basal tree are of slightly lower magnitude than in the apical tree.
Fig. 2.
Photomicrographs of representative dendritic
segments in the lateral branches of the apical dendritic tree from a
CA1 pyramidal cell in an OVX+O (A) and an OVX+E
(B) animal. Camera lucida tracings of the segment from the
OVX+O (C) and OVX+E (D) cells show all visible
dendritic spines. Some dendritic spines are indicated by
arrows. Note the increased density of dendritic spines on
the dendrites of the cell from an estradiol-treated animal. This
estradiol-induced increase in spine density is quantified in Figure 3.
Scale bar, 10 µm (applies to all panels).
[View Larger Version of this Image (56K GIF file)]
Fig. 3.
Bar graphs depicting the mean difference in
dendritic spine density in the apical dendritic trees of CA1 pyramidal
cells from ovariectomized, oil-treated (OVX+O), and
ovariectomized, estradiol-treated (OVX+E) animals. All well
filled CA1 pyramidal cells in this study were included. The difference
in mean dendritic spine density is 22%; **p < 0.001.
[View Larger Version of this Image (65K GIF file)]
Association of dendritic spine density and
intrinsic properties
Analysis of the association of CA1 pyramidal cell intrinsic
properties with dendritic spine density revealed a correlation only
with cellular input resistance. Relating input resistance to dendritic
spine density on 31 well filled CA1 pyramidal cells revealed a weak
negative association (R = 0.50, p < 0.01; Fig. 4, Table 1). Although spine
density was negatively associated with input resistance, and there was
a significant difference in mean spine density between cells from OVX+O
and OVX+E animals, no significant difference in mean input resistance
in cells from OVX+O and OVX+E animals was observed. This finding is
consistent with the previous observations of others (Wong and Moss,
1992). In contrast to input resistance, no other intrinsic
electrophysiological parameter measured (resting membrane potential,
time constant, mV to threshold, action potential amplitude or duration,
spike afterhyperpolarization amplitude or duration) was significantly associated with dendritic spine density (Fig. 3, Table 1). However, in
cells with increased dendritic spine density, there were statistical trends toward more hyperpolarized resting potential, increased action
potential amplitude, and decreased action potential duration (Table 1).
Given these trends, we repeated some measurements with cells held at
approximately the same membrane potential (60 mV); in these cells,
the significant negative relationship between input resistance and
spine density remained (R = 0.46, p < 0.05; data not shown).
Fig. 4.
Representative intracellular recordings from CA1
pyramidal cells in slices from an OVX+O (A) and OVX+E
(B) animal. Recordings were made from the resting membrane
potential in standard ACSF. In each panel, the top traces
are voltage and the bottom traces are current. Calibration
pulse, 10 mV, 10 msec. Note that input resistance is greater in the
cell in A (OVX+O), which has a lower density of dendritic
spines than the cell in B (OVX+E), which has higher spine
density. C shows the negative correlation between input
resistance and dendritic spine density in CA1 pyramidal cells. Data
from cells in OVX+O (open squares), OVX+E
(filled squares), and gonadally intact (open
circles) animals are plotted together. Although there is a
significant correlation between spine density and input resistance,
there is no significant difference in mean input resistance between
cells from OVX+O and OVX+E animals (see text).
[View Larger Version of this Image (20K GIF file)]
Table 1.
Association of CA1 pyramidal cell intrinsic properties with
dendritic spine density
|
|
|
|
| Input
resistance |
R = 0.50 |
p < 0.01 |
| Time constant |
R = 0.13 |
p > 0.10 |
| Resting membrane
potential |
R = 0.36 |
p < 0.10 trend |
| mV to threshold |
R = 0.25 |
p > 0.10 |
| Action potential amplitude |
R = 0.38 |
p < 0.10 trend |
| Action potential
duration |
R = 0.39 |
p < 0.10 trend |
| Afterhyperpolarization amplitude |
R = 0.07 |
p > 0.10 |
| Afterhyperpolarization
duration |
R = 0.23 |
p > 0.10 |
|
|
The association of CA1 pyramidal cell intrinsic
electrophysiological properties with dendritic spine density was
determined by linear regression analysis of each property on spine
density for CA1 pyramidal cells. R values and significance
levels are shown. A significant negative association between cellular
input resistance and dendritic spine density was observed.
Additionally, statistical trends toward significant association between
spine density and resting membrane potential, action potential
amplitude, and action potential duration were detected.
|
|
There are at least two possible sources of the negative association
between spine density and input resistance: (1) increased dendritic
membrane surface area of cells with more spines could contribute to
decreased input resistance, and/or (2) increased background synaptic
activity onto cells with greater dendritic spine density could result
in a lower measured input resistance. The observation that input
resistance, but not time constant, was significantly associated with
differential spine density suggested that increased membrane surface
area was the major contributor to this relationship. To determine the
effect of background synaptic activity on input resistance in the
slice, 10 additional cells (4 OVX+O, 4 OVX+E, 2 intact) were analyzed
in recording medium containing 2 mM kynurenic acid to block
glutamate receptors and thereby decrease background synaptic activity.
Under these conditions, the negative association between input
resistance and dendritic spine density remained (R = 0.55, p < 0.01), indicating that the background
synaptic activity was not a major contributor to this negative
relationship.
Additionally, no differences in the overall two-dimensional dendritic
length of the apical, basal, or combined apical and basal dendritic
trees were observed in CA1 pyramidal cells from OVX+O and OVX+E
animals, consistent with previous observations from Golgi-impregnated
tissue (Woolley and McEwen 1994); nor was any association observed
between total dendritic length and dendritic spine density. These two
observations indicate that potential differences in dendritic length
cannot be responsible for the relationship between input resistance and
spine density observed in these experiments.
Glutamate receptor binding
Because dendritic spines are sites of excitatory synaptic
input and because a majority of excitatory synapses in CA1 st. radiatum are glutamatergic, we determined whether glutamate receptor binding increases in parallel with dendritic spine and synapse density after
ovarian steroid treatment. Quantitative analysis of NMDA-displaced [3H]glutamate binding in the st. radiatum of the CA1
region of the hippocampus revealed a significant overall effect of
hormone treatment (F(2,24) = 6.74, p < 0.01). NMDA receptor binding in estradiol-treated rats was 30% greater than that in ovariectomized controls
(p < 0.01; Figs. 5,
6A). NMDA receptor
binding in the st. radiatum of animals treated with estradiol followed
by progesterone was intermediate between levels in estradiol-treated
and control animals (Fig. 6A). A significant overall
effect of hormone treatment was also observed in NMDA receptor binding
in the st. oriens (F(2,24) = 15.962, p < 0.01). In this case, estradiol treatment resulted in a 46% increase in NMDA receptor binding ( p < 0.01; Figs. 5, 6A). These results are consistent with
previous observations of Weiland (1992a).
Fig. 5.
Representative autoradiograms of total
[3H]glutamate binding in the hippocampus of
ovariectomized rats treated with sesame oil (A) or estradiol
(B) and the [3H]glutamate binding that remains
after displacement with NMDA in OVX+O (C) or OVX+E
(D) animals. Agonist binding to the NMDA receptor was taken
to be the amount of total glutamate binding that was displaced by NMDA,
i.e., the difference between the top and bottom
panels. Note that total glutamate binding is increased by
estradiol treatment and that this difference is attributable to
enhanced NMDA binding because there is no difference between OVX+O and
OVX+E in the binding that remains after displacement with NMDA.
NMDA-displaceable [3H]glutamate binding within the CA1
region (indicated by arrows) is quantified in Figure
6A.
[View Larger Version of this Image (151K GIF file)]
Fig. 6.
Bar graphs depicting the effect of estradiol and
progesterone treatments on NMDA-displaceable
[3H]glutamate (A) and [3H]AMPA
(B) binding in the regions of the hippocampus containing the
apical (str. radiatum) or basal (str.
oriens) dendrites of CA1 pyramidal cells. Filled
bars represent binding in OVX+O animals; stippled bars
represent binding in OVX+E animals; open bars represent binding in ovariectomized animals treated with both estradiol and
progesterone (OVX+EP). Note that treatment with either estradiol or
estradiol plus progesterone increases NMDA receptor binding with no
effect on AMPA receptor binding. **, Significant difference from OVX+O
(p < 0.01); *, significant difference from
OVX+O (p < 0.05).
[View Larger Version of this Image (21K GIF file)]
In alternate sections of the same hippocampi in which these
hormone-induced changes in NMDA receptor binding were observed, no
changes in [3H]AMPA binding were detected. One-way ANOVA
indicated no significant overall effect of hormone treatment in either
the st. radiatum or the st. oriens for [3H]AMPA binding
(p > 0.1; Fig. 6B).
Association of dendritic spine density with
synaptic properties
Anatomical studies suggest that new dendritic spines and synapses
induced by estradiol represent functional contacts (Woolley and McEwen,
1992). Furthermore, estradiol treatment increases NMDA receptor binding
in parallel with dendritic spine and synapse density. Given these
findings, one would expect increased dendritic spine density to be
correlated with increased sensitivity to synaptic input. We tested the
relationship between dendritic spine density and the efficacy of
synaptic input onto CA1 pyramidal cells using full I/O curves. A
bipolar stimulating electrode was placed on the surface of the slice to
activate the Schaffer collateral fibers. In initial experiments, the
relationship between the intensity of a stimulus delivered to the slice
and the amplitude of the presynaptic fiber volley evoked in CA1 st.
radiatum was tested. This relationship was linear over a wide range of
stimulus intensities (data not shown). Linearity of the relationship
between stimulus intensity and fiber volley amplitude validated
comparison of the slope of the intracellularly recorded EPSP to
stimulus intensity in an I/O curve. Intracellular EPSPs were recorded
in 11 well filled CA1 pyramidal cells (5 OVX+O, 4 OVX+E, 2 intact)
beginning from a stimulus intensity that generated no detectable
response to that which generated a maximal EPSP. When dendritic spine
density was related to the slope of an I/O curve generated from EPSP
initial slope (Fig. 7A,B) or amplitude (data
not shown), no consistent relationship was observed (Fig.
7C; R = 0.15, p > 0.1 ).
Thus, recording in standard medium and from a relatively hyperpolarized membrane potential, we were unable to detect a relationship between dendritic spine density and sensitivity to synaptic input.
Fig. 7.
A shows representative intracellular
recordings from a CA1 pyramidal cell recorded in standard ACSF.
Calibration pulses in top (voltage) traces
indicate 10 mV, 10 msec, in bottom (current) trace 1.0 nA, 10 msec. Stimuli of increasing intensity
(indicated at the left of each trace) were delivered to the
CA1 st. radiatum embedded in a 100 msec, 0.5 nA hyperpolarizing current
pulse. EPSP (indicated by arrowheads in A) slope
was plotted versus stimulus intensity to generate input/output curves
(B). The slope of such intracellular input/output curves was
taken as a measure of sensitivity to synaptic input. No correlation
between input/output curve slope and dendritic spine density was
observed under standard recording conditions (C).
[View Larger Version of this Image (21K GIF file)]
The effect of estradiol to increase binding to NMDA receptors,
but not to AMPA receptors, suggested that the dendritic spines and
synapses induced by estradiol might be specifically enriched in NMDA
receptors. If this were the case, then one would not necessarily expect
to observe a correlation between spine density and the slope of an I/O
curve generated in normal recording medium and from a relatively
hyperpolarized membrane potential. Under these standard recording
conditions, the CA1 pyramidal cell EPSP is composed of AMPA and NMDA
receptor-mediated components and is terminated in part by the
GABAA receptor-mediated IPSP. The initial component of the
EPSP, as measured above, is dominated by the AMPA component. Because of
the voltage-dependent Mg2+ block of the NMDA receptor, this
receptor is largely inactivated at hyperpolarized membrane potentials.
Because the contribution of NMDA receptors to the CA1 pyramidal cell
EPSP is relatively small near the resting membrane potential, any
differences in synaptic sensitivity dependent specifically on NMDA
receptor-mediated input could easily be missed. To test the possibility
that increased dendritic spine density is associated with increased
sensitivity specifically to NMDA receptor-mediated synaptic input, we
repeated I/O curves under conditions designed to enhance the NMDA
receptor-mediated component of the EPSP. For these experiments,
Mg2+ in the recording medium was reduced to 0.6 mM, 30 µM CNQX and 30 µM
bicuculline were added to the recording medium to block AMPA and
GABAA receptors, respectively, and cells were depolarized to approximately 40 mV. To record EPSPs without contamination from
action potentials, 200 mM QX-314 was included in the
recording electrode to block sodium channels in the recorded cell.
Stimulation in the st. radiatum under these recording conditions
produced a prolonged EPSP that was blocked by addition of 50 µM 2-amino-5-phosphopentanoic acid (APV; Fig.
8A). I/O curves were generated for
OVX+O and OVX+E cells from series of NMDA receptor-mediated EPSPs (Fig.
8B).
Fig. 8.
A shows representative intracellular
recordings of NMDA receptor-mediated EPSPs (indicated by
arrowheads) from a CA1 pyramidal cell. Calibration pulse, 10 mV, 10 msec. Stimuli of increasing intensity were delivered to the st.
radiatum to generate input/output curves (B). Stimulus
intensities are indicated at the left of the each trace.
NMDA receptor-mediated EPSPs were recorded with the following
modifications of the recording medium: 30 µM CNQX, 30 µM bicuculline (BMI), Mg2+ reduced to 0.6 mM; in addition, recorded cells were depolarized to
approximately 40 mV and 200 mM QX-314 was included in the recording electrode to eliminate Na+ action potentials in
the recorded cell. EPSPs generated under these conditions were blocked
by addition of 50 µM APV to the recording medium.
B shows representative input/output curves from cells in
slices from OVX+O and OVX+E animals. Note that the slope of the
input/output curve generated from NMDA receptor-mediated EPSPs is
greater in the OVX+E cell.
[View Larger Version of this Image (14K GIF file)]
Quantitative analysis of the relationship between dendritic spine
density and I/O slope generated from NMDA receptor-mediated EPSPs in 17 cells (7 OVX+O, 7 OVX+E, 3 intact) revealed a significant correlation
(R = 0.65, p < 0.01; Fig
9A). Additionally, a significant difference
in mean I/O slope between OVX+O and OVX+E cells (T = 3.473, p < 0.01; Fig. 9B) was observed.
The mean slope for OVX+O cells was 0.41 compared to 0.92 for OVX+E
cells. These results indicate that estradiol treatment results in
increased sensitivity of CA1 pyramidal cells to NMDA receptor-mediated
synaptic input and that this increase is well correlated with the
estradiol-induced increase in dendritic spine density in the apical
dendritic tree of these cells.
Fig. 9.
A shows the correlation between the
slope of input/output curves generated from NMDA receptor-mediated CA1
pyramidal cell EPSPs and dendritic spine density on each cell. Data
from cells in OVX+O (open squares), OVX+E
(filled squares), and gonadally intact
(open circles) animals are plotted together. B is
a bar graph depicting the mean slope of input/output curves generated from NMDA receptor-mediated EPSPs in cells from OVX+O compared to OVX+E
animals. Note that the mean slope of the input/output curves generated
from NMDA receptor-mediated EPSPs is significantly greater in the cells
from OVX+E animals; ** p < 0.01.
[View Larger Version of this Image (21K GIF file)]
DISCUSSION
The results presented in this study demonstrate that differences
in numbers of dendritic spines on hippocampal CA1 pyramidal cells are
associated with differences in both the intrinsic and the synaptic
properties of these cells. These findings represent the first attempt
to determine the functional contribution of additional dendritic spines
and synapses to the physiology of hippocampal neurons. In this study,
we found that cellular input resistance is negatively correlated with
dendritic spine density. This negative correlation is consistent with
the interpretation that increased numbers of dendritic spines result in
increased dendritic surface area and, thus, decreased input resistance; increased background excitatory synaptic activity was ruled out as a
possible source of the correlation. Additionally, in agreement with
previous binding studies (Weiland, 1992a), our results from glutamate
receptor autoradiography indicated that estradiol increases binding to
the NMDA but not the AMPA subtype of glutamate receptor. The lack of an
estradiol effect on AMPA receptor binding suggested that the
sensitivity of CA1 pyramidal cells to synaptic input under normal
conditions, in which the AMPA receptor-mediated component of the EPSP
is dominant, would not be altered by estradiol treatment. We assessed
the sensitivity of CA1 pyramidal cells to synaptic input using full I/O
curves. In initial experiments, recording in standard ACSF and at a
membrane potential near the resting potential, no correlation was
observed between the slope of an I/O curve and dendritic spine density,
as predicted from the binding results. However, the estradiol-induced
increase in NMDA receptor binding suggested that NMDA receptor-mediated
EPSPs might be influenced by estradiol. When recording conditions were
altered to enhance the NMDA receptor-mediated component of the EPSP, we
observed a significant correlation between I/O slope and dendritic
spine density. Furthermore, this relationship translated into a
significant increase in mean I/O slope between cells from OVX+O and
OVX+E animals. These results confirm that estradiol increases dendritic spine density on CA1 pyramidal cells and further demonstrate that this
increase in spine density is well correlated with sensitivity to NMDA
receptor-mediated synaptic input.
There are several lines of evidence indicating that estradiol treatment
may increase numbers of NMDA receptors in the hippocampal CA1 region.
First, it has been shown previously that the estradiol-induced increase
in NMDA receptor binding in CA1 reflects an increase in
Bmax rather than an affinity change in the
receptor (Weiland, 1992a). Second, it was reported recently that
immunofluorescence for NMDA receptor subunit 1 (NMDAR1), an obligatory
subunit of the NMDA receptor complex, is upregulated in the CA1 region
by estradiol treatment (Gazzaley et al., 1996). These observations, in
combination with our morphological, binding, and electrophysiological results, suggest an increase in NMDA receptor number. However, it
should be noted that neither binding nor immunohistochemistry (at the
light microscopic level) can distinguish between synaptic and
nonsynaptic receptors; thus, it cannot be assumed that all receptors
detected histologically contribute to synaptic responses.
There is also evidence to suggest that estradiol may regulate the NMDA
receptor and spine/synapse number, at least in part, independently.
First, Gazzaley et al. (1996) observed an estradiol-induced increase in
NMDAR1 immunofluorescence in the cell body as well as dendritic layers
of CA1, and an increase in the dentate gyrus cell body layer (although
spine changes are not observed in granule cells). Second, the increase
in NMDA receptor binding is of slightly greater magnitude than the
morphological change. However, even if the estradiol-induced increases
in NMDA receptor binding and NMDAR1 immunofluorescence are relevant to
processes other than increased numbers of dendritic spines, the
increases in binding and NMDAR1 immunofluorescence in CA1 are likely to
be involved in the increased sensitivity of CA1 pyramidal cells to NMDA
receptor-mediated synaptic input.
The observations that estradiol specifically increases NMDA receptor
binding as well as sensitivity specifically to NMDA receptor-mediated synaptic input suggests the possibility that the new dendritic spines
and synapses induced by estradiol treatment could be a specialized
subpopulation of contacts in which the NMDA receptor is dominant. This
suggestion appears to contradict the generally held notion that NMDA
and non-NMDA receptors are colocalized at excitatory synapses in the
hippocampus as determined from analysis of miniature EPSCs in cultured
hippocampal neurons (Bekkers and Stevens, 1989). However, such
colocalization of receptor types may not be the case for all
hippocampal spine synapses. Indeed, Bekkers and Stevens (1989) found
colocalization of NMDA and non-NMDA receptors at ~70% of excitatory
synapses; 20% of synapses appeared to be non-NMDA and 10% pure NMDA
synapses. Second, proportions of synapses in which receptor types are
colocalized may differ between cultured cells and cells in the acute
hippocampal slice or the hippocampus in vivo. Furthermore, a
population of "silent" synapses on CA1 pyramidal cells that, in
hippocampal slices, apparently mediate pure NMDA receptor EPSCs has
recently been electrophysiologically demonstrated (Isaac et al., 1995;
Liao et al., 1995). It seems plausible that the new dendritic spines
and synapses induced by estradiol treatment represent such a
subpopulation of pure NMDA synapses. However, it should be mentioned
that our data cannot distinguish between the possibility that estradiol
induces a specialized subpopulation of synapses at which the NMDA
receptor dominates the postsynaptic response and, alternatively,
uniformly increases the contribution of the NMDA receptor at synapses
containing both NMDA and non-NMDA receptor types.
In previous reports, we have hypothesized that estradiol induction of
new dendritic spines and synapses could provide a structural mechanism
by which estradiol exerts its effects on hippocampal physiology.
Estradiol has been shown to increase hippocampal excitability as
demonstrated by facilitation of kindled seizure acquisition in the
hippocampus (Buterbaugh and Hudson, 1991), increased severity of kainic
acid-induced seizures (Nicoletti et al., 1985), and decreased
hippocampal seizure threshold (Terasawa and Timiras, 1968).
Furthermore, during the estrous cycle, in which spine and synapse
density fluctuate naturally with changing hormone levels (Woolley et
al., 1990), the threshold for hippocampal seizure activity decreases
(Terasawa and Timiras, 1968) and LTP is enhanced (Warren et al., 1995)
as spine and synapse density increase. Interestingly, Wong and Moss
(1992) previously reported that ~20% of CA1 pyramidal cells in
hippocampal slices from estradiol-treated rats showed prolonged EPSPs
in response to Schaffer collateral stimulation. These authors suggested
that such prolonged responses could be attributable to enhanced NMDA
receptor activation. Because the recordings in that study were made
from a membrane potential near the resting potential (i.e., the cells
were relatively hyperpolarized), it is possible that some NMDA
contribution went undetected because of the voltage dependence of the
NMDA receptor.
The possibility that the new spines and synapses induced by estradiol
are enriched in NMDA receptors is consistent with the electrophysiological findings mentioned above. The types of stimuli that have been used to detect estradiol's effects on hippocampal physiology, i.e., seizure- or LTP-inducing stimuli, are those that
produce substantial postsynaptic depolarization and thus are likely to
be affected by putative pure NMDA receptor synapses. The possibility
that ovarian steroids induce synapses at which NMDA receptors dominate
has been suggested previously by Warren et al. (1995) to be involved in
differences in LTP across the estrous cycle. In this study, animals in
different phases of the estrous cycle showed no differences in a
pre-LTP I/O curve generated with low-frequency test stimuli. However,
animals in the proestrus phase of the cycle, the phase in which spine
and synapse density are elevated (Woolley et al., 1990; Woolley and
McEwen, 1992), show greater potentiation after a tetanic stimulus than
animals in other phases of the cycle (Warren et al., 1995). Warren et al. suggested that, in the proestrus animals, a new population of
synapses in which NMDA receptors are the dominant or active receptor
type may be available to be potentiated. Our results are consistent
with this suggestion.
This effect of estradiol, to enhance sensitivity of CA1 pyramidal cells
to NMDA receptor-mediated synaptic input, is not mutually exclusive
with other mechanisms by which estradiol treatment may alter
excitability of these cells. The most likely additional mechanism by
which estradiol may act is through regulation of inhibition of CA1
pyramidal cells. It is the interneurons in the CA1 region that have
been shown to concentrate radiolabeled estradiol and, therefore, are
most likely to possess classical estradiol receptors (Loy at al.,
1988). Furthermore, estradiol has been shown to regulate levels of
glutamic acid decarboxylase mRNA in CA1 cells (Weiland, 1992b) as well
as GABAA receptor binding in CA1 (Schumacher et al.,
1989).
The mechanism by which estradiol induces new dendritic spines and
synapses on hippocampal CA1 pyramidal cells is still unclear. Estradiol
induction of dendritic spines could be initiated through direct,
nongenomic action (see, for example, Wong and Moss, 1992; Gu and Moss,
1996), through a mechanism involving inhibition (or disinhibition), or
by some other, as yet unidentified, mechanism. In a recent report,
Murphy and Segal (1996) demonstrated estradiol induction of dendritic
spines on hippocampal pyramidal cells in vitro. Hippocampal
neurons cultured for several days in the presence of estradiol show
increased dendritic spine density compared to cells in control
cultures. Estradiol induction of dendritic spines in vitro
may be similar to estradiol's effects in vivo because both
occur on a similar time scale; further, both the in vitro (Murphy and Segal, 1996) and in vivo (Woolley and McEwen,
1994) effects are blocked by NMDA receptor antagonists. The in
vitro induction of dendritic spines by estradiol may provide a
useful system in which to address the molecular mechanism(s) by which estradiol induces new dendritic spines.
In summary, the results presented here represent the first
attempt to define the functional consequences of estradiol-induced dendritic spines and synapses on hippocampal CA1 pyramidal cells. Our
results demonstrate that estradiol treatment increases the sensitivity
of CA1 pyramidal cells to NMDA receptor-mediated synaptic input,
possibly via induction of a specialized subpopulation of dendritic
spines containing synapses at which NMDA rather than non-NMDA glutamate
receptors are the dominant receptor type. Although these synapses may
not be active under baseline conditions, they could be recruited under
conditions of increased postsynaptic depolarization. As such, these
synapses may be involved either in learning and memory processes as
reflected by LTP or in seizure generation. The significance of such
synapses in the normal functioning of the hippocampus remains to be
determined.
FOOTNOTES
Received Sept. 12, 1996; revised Dec. 12, 1996; accepted Dec. 19, 1996.
This research was supported by National Institutes of Health Grants NS
18895 to P.A.S. and NS 09787 to C.S.W.
Correspondence should be addressed to Catherine S. Woolley, Department
of Neurological Surgery, Box 356470, University of Washington, Seattle,
WA 98195.
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R. Bi, M. R. Foy, R.-M. Vouimba, R. F. Thompson, and M. Baudry
Cyclic changes in estradiol regulate synaptic plasticity through the MAP kinase pathway
PNAS,
November 6, 2001;
98(23):
13391 - 13395.
[Abstract]
[Full Text]
[PDF]
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Compound via MeSH
