Published online before print April 14, 2003, doi: 10.1161/01.HYP.0000069007.98987.E0
(Hypertension. 2003;41:1246.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
Structural Changes in AMPA-Receptive Neurons in the Nucleus of the Solitary Tract of Spontaneously Hypertensive Rats
From the Neurological Sciences Institute, Oregon Health and Science University, Beaverton, Ore.
Correspondence to Sue A. Aicher, Neurological Sciences Institute, Oregon Health and Science University, 505 NW 185th Ave, Beaverton, OR 97006. E-mail aichers{at}ohsu.edu
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Abstract |
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The baroreceptor reflex is critical for homeostatic regulation of blood pressure and is initiated centrally by glutamate release from baroreceptive afferents onto neurons in the nucleus of the solitary tract that activates AMPA-type glutamate receptors. The GluR1 subunit of the AMPA receptor is located at postsynaptic sites within the nucleus of the solitary tract, particularly in dendritic spines, which are important sites for synaptic plasticity. We tested whether the distribution of GluR1 changes after sustained hypertension, which alters baroreceptor afferent activity. We examined the distribution of GluR1 in the nucleus of the solitary tract of both hypertensive (spontaneously hypertensive) and normotensive (Wistar-Kyoto) rats at the light microscopic and electron microscopic levels. There were more GluR1-containing dendritic spines in the nucleus of the solitary tract of hypertensive rats compared with normotensive rats, which was attributable to an increase in the proportion of dendritic spines containing GluR1 as well as an increase in the total number of dendritic spines. The differences were only seen after the development of hypertension and were not seen in rostral regions of the nucleus of the solitary tract. In the spontaneously hypertensive rat, many synapses on GluR1-containing dendrites had the morphological features of synapses undergoing dynamic changes, including the presence of perforated synapses. These results suggest that changes in afferent activity to the nucleus of the solitary tract during sustained hypertension alter both the dendritic structure and AMPA receptor content of some neurons. These structural changes may be a substrate for central resetting of the baroreceptor reflex.
Key Words: rats, spontaneously hypertensive • rats, inbred WKY • central nervous system • blood pressure • baroreflex • glutamate receptor
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Introduction |
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Baroreceptors are stretch receptors found in large blood vessels around the heart. Activation of these receptors is relayed to the brain by afferents to the nucleus of the solitary tract (NTS),1 which release glutamate.2,3 A central reflex arc through the brain stem and spinal cord serves to return blood pressure to homeostatic values. Although the underlying of hypertension is likely to be heterogeneous, at least some forms of hypertension may be caused by, or lead to, dysfunction within the central baroreceptor reflex arc.4,5 Functional changes in properties of NTS neurons as well as altered blood pressure responses to glutamate microinjections into this region have been reported during hypertension.6 Although it has been postulated that changes in central autonomic neurons may occur during hypertension,7,8 these changes have been difficult to confirm.4,9
-Amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA)-type glutamate receptors10 are involved in mediating the effects of baroreceptor stimulation within the NTS.11–13 Recent studies have shown that 3 of the 4 known AMPA receptor subunits are present within the NTS.14,15 We have found similar results,16 and we also noted that the GluR1 subunit was most heavily located in dendritic spines, suggesting a potential role for AMPA receptors containing this subunit in synaptic plasticity within the NTS. We set out to determine if structural changes occur in neurons that contain GluR1 and may be an underlying substrate for the neural changes that occur during hypertension, including central resetting of the baroreceptor reflex.
A variety of animal models of hypertension have been developed to facilitate the study of the underlying mechanisms of this disorder. This study used the spontaneously hypertensive rat (SHR), a genetic/developmental model that is probably the most widely used model of hypertension.17 We asked whether a change in the distribution of the AMPA receptor subunit, GluR1, is seen after sustained hypertension. We also tested whether the change was specifically related to hypertension by examining GluR1 in the NTS of young, normotensive SHRs and by examining regions of the NTS that do not receive cardiovascular afferents. We found changes in both the morphology and AMPA receptor content of NTS neurons after sustained hypertension. Because the NTS receives primary baroreceptive afferents that release glutamate, our results support the notion that hypertension can alter the structure, and possibly function, of NTS neurons.
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Methods |
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Subjects
All methods were approved by the IACUC at Weill Medical College of Cornell University, where this work was initiated. Male rats used in these experiments were purchased from Taconic Laboratories (Germantown, NY). Age-matched pairs of SHR and Wistar-Kyoto rats (WKY) were received at either 4 weeks (n=4 pairs) or at 15 weeks (n=4 pairs) of age. Rats were tested and perfused 1 week later, at 5 and 16 weeks of age, respectively.
Assessment of Blood Pressure
Systolic blood pressure was assessed in restrained rats by use of an indirect tail-cuff method (Kent Scientific Corp). The cuff pressure and pulsatile blood pressure signal were detected by a piezoelectric pulse sensor and were monitored on a computer interfaced to an A/D board with Spike 2 software (Cambridge Electronic Design). After the rat was acclimated and a strong pulsatile blood pressure signal was recorded, the tail occlusion cuff was inflated until the pulsatile blood pressure signal was lost and then was released for a gradual deflation (2 to 4 seconds). Systolic pressure was the pressure of the occlusion cuff at which the pulsatile blood pressure signal was again detected. The average systolic pressure for 3 to 6 trials was the systolic pressure for that day. The systolic blood pressure on the last day before perfusion was used for statistical analyses. Systolic pressures between groups were compared by means of a t test, (=0.05).
Perfusion and Immunocytochemistry
Rats were overdosed with sodium pentobarbital (150 mg/kg) and perfused transcardially with the following sequence of solutions: (1) 10 mL heparinized saline; (2) 50 mL 3.8% acrolein in 2% paraformaldehyde; and (3) 200 mL 2% paraformaldehyde (in 0.1 mol/L phosphate buffer). The brain stem was sectioned (40 µm) on a vibrating microtome and collected into 0.1 mol/L phosphate buffer. Sections through the NTS were processed for immunoperoxidase localization18,19 of GluR1. A rabbit polyclonal antibody directed against the R1 (GluR1) subunit of the AMPA receptor20 was obtained from Chemicon and was used at a 1:25 dilution.16 Tissue sections were incubated in the primary antibody for 40 hours at 4°C, and the bound antibody was detected with a biotinylated goat anti-rabbit IgG (1:400; Vector Laboratories).
Light Microscopic Analyses
For GluR1 immunoperoxidase labeling in the NTS, pairs of animals (1 SHR, 1 WKY; same age) were processed through identical immunocytochemical conditions to ensure comparable labeling conditions. A puncture through the brain stem was performed on one brain in each pair, and tissue sections from the 2 animals were combined in the same vials during all antibody incubations. Tissue sections were separated again after the completion of the immunocytochemical procedures by means of the tissue puncture to identify sections from one animal in the pair. Half of the tissue sections were mounted on slides for light microscopic analysis; the other half were prepared for electron microscopic analysis. An observer blinded to the experimental conditions determined the area of the NTS to be examined in a selected tissue section from each animal. To ensure that the volume of NTS did not change, the entire subpostremal region was outlined and the total pixel area of the outlined region was determined with the use of NIH Image software. The outline of NTS excluded the area postrema, the central canal, the dorsal motor nucleus of the vagus, and the dorsal column nuclei. An observer blinded to the experimental condition measured the area of NTS for each case. To determine the number of GluR1-labeled puncta within the NTS, puncta were counted in 2 rectangular regions that were selected from a single vibratome section. Two regions within the medial NTS (0.05 mmx0.1 mm=0.005 mm2), at the level of the area postrema, were examined (Figure 1). One region was located just medial to the solitary tract, whereas the other was located ventrolateral to the area postrema (boxes in Figure 1A). Because the results of GluR1 counts were similar for these 2 subregions, counts were pooled for the final statistical analyses and are shown in the analyses as the combined area (0.01 mm2) of both regions.
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Puncta were counted from a digital image captured with a Spot 2 camera and Twain software (with background subtraction), and counts were verified by 2 independent blinded observers. Punctate profiles were considered small, round regions of intense labeling that were not continuous with other labeled profiles (Figure 1B). Paired t tests were used to compare the number of GluR1-labeled puncta for similar groups, such as 16-week-old SHR versus 16-week-old WKY or 5-week-old SHR versus 5-week-old WKY (=0.05). Because of potential variations in immunocytochemical conditions, comparisons between different runs may lead to invalid comparisons at the light microscopic level. In the current study, all comparisons were made between cases with identical tissue processing conditions (eg, 2 strains at 16 weeks of age or 2 strains at 5 weeks of age).
Electron Microscopy
Tissue sections were osmicated and embedded in plastic after immunocytochemical procedures. Ultrathin sections (75 nm) through the surface of each section were collected onto copper grids, counterstained, and examined with the use of a Phillips CM10 or a JEOL1200EX electron microscope. Only cases with successful labeling and optimal morphological preservation were included in the electron microscopic analysis. For the ultrastructural analysis of the GluR1 labeling in SHR and WKY, a 3025-µm2 area of the medial NTS (3 SHR, 3 WKY at each age) was examined (Figure 1). For each case, a region was selected that contained labeled tissue over one entire grid square (55 µm2) that was at a consistent tissue depth (eg, no plastic regions were seen). For each case, all GluR1-labeled profiles and unlabeled profiles of similar type (eg, dendrites or spines) were counted and measured. Profiles were examined and categorized by an observer who was blinded to the experimental condition. The cross-sectional diameter of dendrites determined their classification as either large (>1.5 µm), small (0.5 to 1.5 µm), or spine (<0.5 µm and receiving an asymmetric synapse21). A 
2 analysis was used to determine if there were different proportions for GluR1-labeled versus unlabeled profiles in SHR versus WKY in the fixed area of tissue. Separate 2 analyses were conducted for each profile type (eg, spines, small dendrites, or large dendrites) and at each age (5 weeks versus 16 weeks). A level of =0.05 was used for all statistical comparisons.
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Results |
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In a previous study,16 we examined the ultrastructural distribution of AMPA receptor subunits that are present in the NTS and are likely candidates for involvement in mediating the baroreflex. The distribution of GluR1 was most intriguing. At the light microscopic level, GluR1 was found primarily in small punctate structures and in cell bodies (Figures 1A and 1B). At the electron microscopic level, GluR1 was found primarily at postsynaptic sites, particularly in small dendrites and dendritic spines (see below). Based on the comparisons between the light microscopic and electron microscopic distributions of GluR1, most of the small punctate structures seen at the light microscopic level probably correspond to small dendrites and dendritic spines. For quantitative analyses, these punctate structures were compared between groups at the light microscopic level, whereas both dendrites and spines were examined at the electron microscopic level.
We first measured systolic arterial pressure in each animal to verify that our SHR were hypertensive at 16 weeks of age but not at 5 weeks of age (Figures 2A and 2B). We then found that there were more GluR1-labeled punctate profiles in the NTS of the hypertensive rats (Figures 2C and 2D) compared with normotensive control animals at the light microscopic level. This increased density of GluR1-labeled puncta per unit area was not due to shrinkage of the nucleus, since there was no difference in the size of NTS between these groups of animals (P=0.40).
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We tested whether these differences in GluR1 puncta density are due to inherent genetic differences between SHR and WKY or may actually be related to blood pressure. If the differences in GluR1 labeling are not related to blood pressure, then in younger animals with similar blood pressure, we should still see differences in GluR1 labeling between the 2 strains. We measured blood pressure in 5-week-old SHR and WKY and then examined their GluR1 puncta density in the NTS. The 5-week-old SHR were not hypertensive (Figure 2A), and they did not have a greater number of GluR1-labeled puncta compared with age-matched WKY (Figure 2C). These results suggest that the differences in GluR1 density are not due to inherent strain differences but are related to the onset of hypertension. This hypothesis is supported by linear regression analyses of blood pressure and GluR1 puncta counts in NTS. At 5 weeks of age, there was no relationship between systolic blood pressure and the number of GluR1 puncta in the NTS (R=0.21), but at 16 weeks of age, there was a strong correlation between blood pressure and GluR1 puncta count (R=0.83). It is apparent from this analysis that across a range in systolic pressures between SHR and WKY at 16 weeks of age, rats with the highest systolic pressures also had the highest GluR1 puncta counts. These results support the hypothesis that GluR1 labeling in the NTS is related to the level of arterial blood pressure.
Comparison of the values for puncta counts in the NTS across ages and rat strains (Figures 2C and 2D) indicates that there are actually more GluR1 puncta in the NTS of both strains at 5 weeks of age (Figure 2C) and there is a decrease in the number of puncta at 16 weeks in the WKY only (Figure 2D). However, this suggestion is not born out at the electron microscopic level (see below), where the number of spines and small dendrites are similar between WKY at both ages. These observations indicate that the detection of GluR1-labeled puncta is somewhat more variable at the light microscopic level and may be due to variations in the immunocytochemical conditions between experiments. This is why only comparisons between cases run under identical immunocytochemical conditions were compared.
If the changes in GluR1-labeled puncta are related to changes in cardiopulmonary or baroreceptor afferent activity, we would expect the increase in GluR1 density to be confined to regions of the NTS that receive baroreceptor afferents. As a control for the specificity of the changes in GluR1 density, we examined GluR1 labeling in the rostral NTS, which receives gustatory rather than baroreceptive afferents. The density of GluR1 puncta in the rostral NTS was similar in 16-week-old SHR (14±2.2 per 0.01 mm2) compared with 16-week-old WKY (12±4.1 per 0.01 mm2). Thus, GluR1 puncta labeling is selectively increased in the region of NTS that receives baroreceptive afferents and is increased only in hypertensive rats.
The above results indicate that there are potentially more GluR1-containing spines in the NTS of SHR after the development of hypertension. We can imagine at least 2 possible scenarios for an increased number of GluR1-containing spines in the NTS after sustained hypertension (although these scenarios are not mutually exclusive). These 2 models are illustrated schematically in Figure 3. The bottom panel of Figure 3 shows the result after hypertension in which there is an increase in the number of GluR1-containing dendritic spines on each neuron. The 2 possible models indicate 2 possible mechanisms: In the first model (Figure 3A), the elevation in blood pressure causes an increase in the synthesis of GluR1 and an enhanced trafficking of the receptor to preexisting spines. In this model (Figure 3A), there is no change in the total number of spines per neuron, but after hypertension, a greater proportion of the spines contain GluR1. In an alternative model (Figure 3B), the elevation in blood pressure leads to an increase in the total number of spines in NTS through the addition of new dendritic spines on each NTS neuron. In this second model, the proportion of spines that contain GluR1 is constant even after the addition of new spines to each neuron (Figure 3B). To determine if there is an increase in spine number or an increased distribution of GluR1 to preexisting spines, we examined the distribution of GluR1 at the electron microscopic level. Both labeled and unlabeled spines are visible with electron microscopy but not with light microscopy.
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Consistent with our light microscopic observations, there was a significant increase in the number of GluR1-labeled spines in SHR compared with WKY in 16-week-old animals but not in 5-week-old animals (Figures 4A and 4B). There were no differences in the number of unlabeled spines between the groups at either age (Figures 4A and 4B). This finding suggests that hypertension leads to both a greater number of spines in the NTS and an increase in the proportion of those spines that contain GluR1 (so both mechanisms illustrated in Figure 3 appear to occur in the NTS after hypertension). This morphological change was specific to spines, since there was not a significant difference between SHR and WKY with regard to the proportion of small dendrites (Figures 4C and 4D) or large dendrites (not shown) containing GluR1. To confirm that these morphological changes were indeed related to blood pressure and not inherent genetic differences, we did similar comparisons between SHR and WKY at 5 weeks of age, before the onset of hypertension in the SHR. There were no differences in GluR1 labeling of spines (Figure 4A) or small dendrites (Figure 4C) at the electron microscopic level between the 2 strains of rats at 5 weeks of age.
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Although not quantitatively assessed, we did note some interesting morphological features in GluR1-labeled spines of hypertensive rats. In normotensive WKY, small dendrites (Figures 5A and 5B) and dendritic spines (Figure 5C) contained GluR1. GluR1-containing dendrites received asymmetric synapses from unlabeled axon terminals, and many of these afferent terminals contained dense core vesicles (Figure 5C). Most of these afferents contacted a single dendritic target (Figures 5B and 5C), but other terminals formed glomeruli with multiple dendritic targets, one or more of which contained GluR1 (Figure 5A). In the SHR, GluR1-containing dendrites also received asymmetric synapses from axon terminals (Figure 6). However, in the SHR, many of these axon terminals formed perforated synapses (Figures 6A and 6B) or exhibited extensive synaptic densities (Figure 6C). Instead of forming typical glomeruli, these afferents often contacted GluR1-containing dendrites that were in direct apposition to each other (Figure 6A). In both WKY and SHR, we often noted that astrocytic glial processes surround both the axon terminal and its dendritic target, particularly at asymmetric synaptic junctions (Figures 5B and 5C). However, in the SHR, these glial processes appeared to be more abundant and possibly enlarged (Figure 6). The morphology of the contacts between unlabeled axon terminals and their GluR1-containing dendritic targets in the SHR is suggestive of snapshots of synapses undergoing plasticity,22,23 potentially in the process of dividing dendritic targets into smaller dendrites or spines.24
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Discussion |
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AMPA receptors in the NTS are critical for baroreceptor transmission11 and are present in baroreceptive neurons15 in the medial NTS. These observations, together with the prevalence of cardiopulmonary and barosensitive neurons within the medial NTS,25 support the notion that many of the AMPA-receptive neurons in the medial NTS are related to cardiovascular function. We found that in the SHR model of hypertension, the number of GluR1-containing spines was increased within the medial NTS. These results indicate that some glutamate-receptive NTS neurons in the hypertensive brain change morphologically, and more spines develop. The majority of these additional spines contained the GluR1 subunit of the AMPA receptor, supporting a role for AMPA receptors in synaptic plasticity22 in the NTS during hypertension.
Our finding of an increase in GluR1 within NTS neurons is in contrast to a recent study26 that found no significant increase in AMPA receptor binding in the NTS of hypertensive animals with radioactive AMPA receptor ligands used to assess binding. However, our results indicate that the increase in receptor density may not be sufficient to be detected with the use of some sampling methods. For example, although we clearly were able to detect an increase in the density of GluR1-labeled spines in the NTS of hypertensive rats, this increase was not sufficient to increase the optical density of GluR1 staining in the whole nucleus. This suggests that changes may be subtle, may occur in only a subset of NTS neurons, and may require different techniques to be detected.
An increase in the number of AMPA receptors might appear to be counterintuitive, since there is a blunting of the baroreflex during hypertension. If AMPA receptors mediate the baroreflex, their increase would be expected to enhance reflex function if they were located on excitatory projection neurons in the NTS. Indeed, a large upregulation of GluR1 and other glutamate receptors in the NTS by heat shock has been reported to augment baroreflex responses.27 However, in the current study, the GluR1 increase was selectively localized to dendritic spines in a subset of neurons. These AMPA receptors on dendritic spines may be calcium permeable, since they appear to lack GluR2 AMPA subunits.16 The calcium signal produced by activation of these receptors may be isolated in the spine, but it is also possible that afferent activation of AMPA receptors on individual spines may have less impact on the postsynaptic cell than activation of synapses on larger dendrites.28–30 We would speculate that the segregation of these GluR1-containing AMPA receptors to dendritic spines could create a situation in which activation of their afferents would have less impact on NTS neurons, except perhaps under conditions in which there is synchronous activation of many of these afferents. This is a feasible mechanism contributing to the decreased sensitivity of the baroreflex during hypertension.
It is possible that the changes in cellular morphology and the changes in receptor distribution are 2 independent events. Factors influencing the formation of dendritic spines may be distinct from mechanisms regulating glutamate receptor trafficking and/or turnover. An alternative mechanism that may lead to an increase in the density of GluR1 would be a reduced turnover of this receptor population. If the mechanisms regulating receptor production are independent, a reduced turnover could lead to an increase in receptor density. However, this would not explain the increase in the formation of dendritic spines.
In other brain regions, increases in dendritic spine density have been correlated with enhanced afferent activation and glutamatergic stimulation.31–33 Recent studies have shown that long-term potentiation leads to an increase in the number of perforated synapses in hippocampal neurons,34 whereas others have shown an increased expression of AMPA receptors in the dendrites of perforated synapses.22 Only recently have attempts been made to determine if changes in spine density lead to changes in the activity of the postsynaptic neurons, and it is clear that we still do not fully understand the function of dendritic spines or the consequences of such structural changes for the neuron.35 However, the evidence strongly suggests that alterations in spine density, together with changes in AMPA receptor distribution, probably are related to changes in the activity of glutamatergic afferents to the neuron. One puzzling aspect of these studies is that the morphological changes seen in the SHR are consistent with an increase in glutamatergic synaptic activity, not a decrease. Aortic baroreceptors are known to reset36 and thus are thought to decrease their activity during hypertension. However, the long-term consequences of hypertension on baroreceptor afferents are not fully understood, nor are the central changes in response to alterations in afferent activity. There also may be increased activity in other glutamatergic afferents to the NTS, such as cardiopulmonary afferents.
The morphology of the GluR1-labeled synapses in SHR was intriguing, and these synapses resemble synapses exposed to increased afferent activity,24 including the abundance of perforated synapses,37 which are thought to be related to plasticity.23 We also noted that the ensheathing of these synapses by glial processes was extensive. Astrocytic processes have long been noted surrounding asymmetric synaptic complexes,38 but in light of recent evidence showing the presence of glutamate transporters39 and receptors on glial processes,20,40,41 it is possible that these astrocytes may play a greater role in shaping these synapses and their function than previously thought possible.42,43
Our results indicate that even at the first relay site of the baroreceptor reflex pathway, there are structural and molecular changes in response to sustained increases in blood pressure. These observations are consistent with previous studies showing altered responses to glutamate injections in the NTS of hypertensive rats8 as well as altered membrane properties of NTS neurons in the hypertensive rat.7 A more recent study has shown altered responses of second-order baroreceptive neurons in another model of hypertension.6 Together these results support the idea that since baroreceptor activity is mediated through glutamate and baroreflex function is altered during hypertension, at least some of these functional changes are manifested in glutamate-receptive neurons within the NTS. Our findings do not preclude the possibility that other receptors may also change within these neurons or that other changes may occur at other sites along the baroreflex arc.
Perspectives
The functional consequences of an increase in spine density and how this alters other components of the reflex pathway, remain to be determined. Even for an individual neuron, we do not understand the functional significance of an increase in spine density. Two recent studies examined spine formation and stability in the living cerebral cortex44,45 and came to dramatically different conclusions.46 The first study44 showed that cortical neurons have a relatively unstable population of dendritic spines, whereas the second study45 concluded that neurons in a different region of the cortex had extremely stable dendritic spines. The meaning of these cellular changes with regard to information storage or relative weighting of synaptic inputs is premature. It will be interesting to see if the structural changes seen in NTS neurons are preventable and/or reversible. Insights will require more detailed information about the morphology of baroreceptive neurons within the NTS, the organization of afferents to these neurons, and the functional consequences of morphological changes in these neurons.
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Acknowledgments |
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Grant support was from the American Heart Association and National Institutes of Health (HL56301). The authors thank Alla Goldberg, James Kraus, Aarti Patel, and Kristin Swanson for technical assistance. Some of the experiments were conducted at the Weill Medical College of Cornell University in the Department of Neurology and Neuroscience, Division of Neurobiology.
Received December 27, 2002; first decision January 24, 2003; accepted March 18, 2003.
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