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. 1997 Mar 1;17(5):1848-59.
doi: 10.1523/JNEUROSCI.17-05-01848.1997.

Estradiol increases the sensitivity of hippocampal CA1 pyramidal cells to NMDA receptor-mediated synaptic input: correlation with dendritic spine density

C S Woolley  1 , N G Weiland, B S McEwen, P A Schwartzkroin
Affiliations

Estradiol increases the sensitivity of hippocampal CA1 pyramidal cells to NMDA receptor-mediated synaptic input: correlation with dendritic spine density

C S Woolley et al. J Neurosci. .

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.

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Figures

Fig. 1.
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 thelower 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).
Fig. 2.
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 byarrows. 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).
Fig. 3.
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.
Fig. 4.
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 tracesare 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).
Fig. 5.
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 Figure6A.
Fig. 6.
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 barsrepresent 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).
Fig. 7.
Fig. 7.
A shows representative intracellular recordings from a CA1 pyramidal cell recorded in standard ACSF. Calibration pulses in top (voltage) tracesindicate 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).
Fig. 8.
Fig. 8.
A shows representative intracellular recordings of NMDA receptor-mediated EPSPs (indicated byarrowheads) 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.
Fig. 9.
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.
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