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1 From the Department of Physiology, Neuroscience Program, and Center for Clinical Neuroscience and Ophthalmology, Michigan State University, East Lansing; and the 2 Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison.
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Abstract |
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METHODS. The monkey model of experimental glaucoma was combined with standard histologic staining and analysis techniques. Fourteen animals were examined.
RESULTS. Mean IOPs higher than 40 mm Hg for 2.5, 4, 8, and 24 weeks resulted in reductions of 10% to 58% in the cross-sectional areas of LGN neurons receiving input from the glaucomatous eye. Reductions for animals with lower mean IOPs (37 and 28 mm Hg) for 16 and 27 weeks were 16% and 30%, respectively. Neurons receiving input from the normal eye also were reduced in size (4–26%). No differential effect in cell size was seen for magnocellular versus parvocellular neurons. Elevation of IOP resulted in an increase in cell density in all layers of the LGN. The increase was approximately two times greater in parvocellular (59%) than magnocellular (31%) layers. When corrected for volumetric shrinkage of the LGN, the estimated loss of neurons was approximately four times greater in the magnocellular than parvocellular layers (38% versus 10%).
CONCLUSIONS. Elevation of IOP affects the size, density, and number of neurons in the LGN, and the volume of the nucleus itself. Although higher mean pressures (more than 40 mm Hg) reduce the period during which these changes occur, comparable damage can be achieved by even moderate (28–37 mm Hg) levels of elevated IOP. On the basis of cell loss, elevation of IOP appears to have a more profound degenerative effect on the magnocellular than on the parvocellular regions of the LGN.
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Introduction |
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In the visual system, as in other parts of the brain, neurons depend on connections with other neurons for proper function and survival. Trauma or disease that affects cells in one area typically also has a degenerative effect on neurons in associated areas.6 7 8 In primary open-angle glaucoma, a disease often characterized by elevated IOP, the primary site of damage appears to be the optic nerve in the region of the lamina cribrosa.9 Because the axons of retinal ganglion cells form the optic nerve, one consequence of glaucoma is the retrograde degeneration of ganglion cells within the retina itself. Although the degenerative effects that elevated IOP has on the optic nerve10 11 and retina12 13 14 are well known, few data are available concerning transynaptic changes within the LGN.15 16 17 To examine these changes, we compared the size, density, and number of neurons in the M- and P-layers of normal monkeys and monkeys with experimental glaucoma.
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Materials and Methods |
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At least once per week after laser treatment, the normal and treated eyes were examined with the slit lamp, and corneal clarity, anterior chamber cells, and flare were noted. After measurement of IOP, the anterior chamber angle and optic nerve head were examined with a goniolens (Zeiss; or model OG3M-13; Ocular Instruments, Inc., San Jose, CA). Fundus photographs were obtained every 3 to 4 weeks, depending on the clinical appearance of the optic disc compared with its appearance in previous eye examinations.
After 2.5 to 27 weeks of elevated IOP, the animals were anesthetized deeply with ketamine HCl (15 mg/kg, intramuscularly), followed by intravenous pentobarbital sodium (35 mg/kg). The eyes then were removed for intracellular analysis,14 and the animals were perfused transcardially with 0.5 l of 0.9% saline followed by 1 to 2 l of 10% formol-saline solution. The brains were removed and postfixed for 4 to 6 weeks with several changes of fresh fixative.
Tissue Processing and Correction for Shrinkage
After fixation, each brain was blocked in the frontal plane,
dehydrated in a series of graded alcohols, and embedded in celloidin.
The LGNs then were sectioned serially at 25 µm in the coronal plane,
and every fifth section was stained with thionine, mounted on a glass
slide, and coverslipped for histologic analysis. Care was taken to
standardize the dehydration and celloidin processing times for each
brain.
Linear tissue shrinkage, assumed to be uniform, was determined by inserting a pair of fine tungsten wires into each block of LGN tissue and carefully measuring the distance between the wires, at the level of the tissue, before and after the dehydration and celloidin embedding processes. The percentage linear shrinkage for each block of tissue then was derived from the formula SL = 100 - (AP/BP x 100), where BP and AP represent the before and after processing distances between the tungsten wires, respectively. On the basis of linear shrinkage (SL), it then was possible to derive correction factors for both areal and volumetric shrinkage. The correction factor for areal shrinkage (ACF = 1/(1 - SL)2, when multiplied by the measured area of each neuron or LGN region (M or P), then yielded the true area of that structure. The correction factor for volumetric shrinkage was derived from the measurement of linear shrinkage (SL) using the formula: VCF = 1/(1 - SL)3.
Cell Size
The effects of elevated IOP on cell size were studied by measuring
at x1000 the cross-sectional areas of approximately 2400 geniculate
neurons in each animal. Because glaucomatous visual field loss is most
common within the central 30°,21
all neurons were sampled
from a rostral–caudal location of the nucleus that corresponded to a
visual field representation of approximately 10 to 15°
azimuth.22
23
24
In addition, because retinal ganglion cell
loss in glaucoma can be diffuse, LGN regions representing retinal input
from superior retina (nasal LGN), inferior retina (temporal LGN), nasal
retina (contralateral LGN), and temporal retina (ipsilateral LGN) were
examined (Fig. 1)
. Cell samples (approximately 100 neurons/layer) were taken from the
full width of each lamina and included only those neurons with clearly
visible nucleoli. Measurements of soma area were obtained from the cell
drawings using a digitizing tablet and commercial software (SigmaScan;
Jandel Scientific, Corte Madera, CA). All cell area measurements were
corrected for tissue shrinkage.
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LGN Volume
LGN volume was determined by capturing digital images of each LGN
sample section using a high-resolution video camera (model C5985
chilled CCD; Hamamatsu, Bridgewater, NJ) and image analysis software
(Image-Pro Plus; Media Cybernetics, Silver Spring, MD). The laminar
area of the M and P region included in each section was obtained by
measuring the total area of each region and subtracting that portion
occupied by interlaminar space. Total laminar volumes for the M and P
regions of each animal were derived by summing the measured areas,
multiplying by section thickness (25 µm), and correcting for sample
size (every fifth section) and volumetric tissue shrinkage.
Statistical Comparisons
All data are presented as means ± 1 SD. Differences in mean
soma size and cell density were compared using two-way analysis of
variance (ANOVA) statistical methods (SPSS, Chicago, IL) combined with
the Bonferroni adjustment for multiple comparisons (NCSS 2000,
Kaysville, UT). Paired comparisons of LGN cell size distributions were
made using the Kolmogorov–Smirnov test for two independent samples
(SPSS). Differences in LGN volume and cell number were compared using
one-way ANOVA, followed by the Dunnett test for multiple comparisons
(SPSS). Correlation and partial correlation analyses (SPSS) were used
to compare the relations between mean, peak, and duration of elevated
IOP; cell size, density, and number; and LGN volume. In all cases,
P = 0.05 was used as the level of significance.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Chronic elevation of IOP also resulted in a decrease in the mean soma sizes of LGN neurons receiving input from the normal eye (Fig. 4) . The percentage difference in soma size for both M- and P-cells within the affected versus unaffected layers was small after 2.5 to 4 weeks of elevated IOP (3.6–5.3%). This difference increased to approximately 14% by 8 weeks, and to 48% after 24 weeks. Animals with 16 weeks of elevated IOP also showed decreased mean soma sizes in both the affected and unaffected layers. Neurons in the unaffected M- and P-layers showed an approximately 12% decrease in mean soma size, and those in the affected layers were 16% smaller than normal. Despite mean IOPs of only approximately 28 mm Hg, and their showing little change in cup-to-disc ratio (Table 1) , the animals with 27 weeks of elevated IOP showed approximately a 26% decrease in M-cell size and a 34% decrease in P-cell size for both affected and unaffected layers.
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LGN Volume.
Figure 7
shows the effects that different levels and durations of elevated IOP
have on LGN volume. As indicated in the Materials and Methods section,
these data represent the total laminar volume (affected and unaffected
layers) for each region. This served to minimize errors in identifying
affected versus unaffected layers in regions of the LGN containing
laminar discontinuities (e.g., Fig. 2C
). As with cell density, all
volumetric data were derived from the right LGN of each animal.
However, comparable measurements from the left LGN of four animals
(normal, 8, 16, and 27 weeks) indicated no left–right bias.
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Neuronal Number.
Estimates of total cell number in the LGNs of normal and glaucomatous
animals were determined from the cell density and LGN volume
measurements, after corrections for tissue shrinkage (Fig. 8)
. For normal animals, the total number of neurons in the LGN was
estimated to be approximately 1.27 million, with 10.3% located in the
M-layers and 89.7% in the P-layers. Compared with matched normal
layers, the affected M-layers of glaucomatous animals showed a
significant decrease (38%) in the number of surviving neurons for each
period studied, whereas the P-layers did not (10% decrease).
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Discussion |
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The cell size data reveal two important relationships between elevation of IOP and LGN degeneration. First, they show that longer durations of elevated IOP, even at low to moderate levels, resulted in larger reductions in the soma sizes of both M- and P-cells. Second, they indicate that higher mean levels of IOP shortened the time during which the cellular changes occur. Animals with 2.5 weeks of elevated pressure at mean levels of approximately 45 mm Hg showed decreases in mean soma size that were comparable with animals with 16 weeks of elevated IOP and mean levels of approximately 36 mm Hg. Similarly, animals with 8 weeks of elevated IOP (approximately 46 mm Hg) displayed reductions in mean soma size that were comparable with those with 27 weeks of elevated IOP and mean IOPs of approximately 28 mm Hg.
At each of the different periods studied, similar percentage decreases in mean cell area were measured in both the M- and P-layers. Although this suggests that IOP affects the sizes of M- and P-cells equally, it is important to note that these data reflect changes in the population mean and not necessarily those of single neurons. This distinction is important, because different populations of neurons may reach their final mean sizes through completely different mechanisms (e.g., cell loss versus shrinkage). The histograms in Figure 5 suggest that both cell loss and shrinkage contribute to the decrease in mean soma size within the M- and P-layers in glaucoma. They also indicate that in both regions the largest neurons may be affected most severely. Both areas show an absence of very large neurons, and both display modest increases in the percentage of small to medium sized neurons, as would be expected if larger neurons also were shrinking (cf., Figs. 5B 5D ). That cell size, and not cell class, may be the main factor governing glaucomatous changes in the LGN is consistent with similar results in the primate retina.12 13 The leftward shift of the lower ends of the parvocellular, but not magnocellular, distributions for animals with 4, 8, and 24 weeks of elevated IOP suggests that general cell shrinkage might play a greater role in determining final mean soma size in the P-layers, whereas cell loss is the primary mechanism in the M-layers. This would be consistent with our cell number estimates: We found approximately a four times greater loss of M-cells than P-cells in the glaucomatous animals.
To date, only one study has examined cellular changes in the primate LGN with glaucoma. Chaturvedi et al.15 used human autopsy material to compare the density of neurons in the magno- and parvocellular regions of normal patients and patients with documented glaucoma. Based on a small (approximately 1 neuron/per square millimeter) but significant decrease in cell density in the M- but not P-layers, the authors concluded that glaucoma has a preferential effect on the M-region of the LGN. Our data also indicate that glaucoma has a differential effect on M- versus P-cell density. However, they show that chronic elevation of IOP results in an increase in LGN cell density and that this increase in cell density is approximately two times greater in the P-layers than in the M-layers (59% versus 31%). The large increase in P-cell density most likely resulted from a significant decrease in laminar volume, but not cell number, in this region of the nucleus, whereas the modest increase in M-cell density probably reflected a complex balance between decreasing laminar volume and cell loss (Figs. 7 8) . As expected, the largest increases in cell density were measured in the unaffected M- and P-layers, where cell loss was minimal.
The apparent contradiction between our cell density results and those of Chaturvedi et al.15 could be explained by animal–human variation or differences in the duration of glaucoma for their patients (years) versus our animals (weeks). If during the initial stages of the disease process, cell density is influenced primarily by a rapid reduction in LGN volume due to early axonal degeneration (described later), then the increases in cell density reported here would be expected. As the disease progresses and cell loss becomes more prevalent, then either no change or a decrease in cell density might be expected, depending on the relation between LGN volume and cell number. This most closely reflects the results of Chaturvedi et al.15
In agreement with Ahmad and Spear,23 we found the total laminar volume of the normal rhesus LGN to be approximately 68 mm3. After only 2.5 weeks of elevated IOP, the volume of the P-layers decreased approximately 23%, whereas the M-layers underwent a 35% reduction in size. Despite its smaller percentage decrease, the actual reduction in P volume is approximately threefold greater than the reduction in M volume (13 mm3 versus 4.2 mm3). Because P-cells undergo little change in size or number during this period (Figs. 4 8) , this initial decrease in P volume most likely reflects an early loss of axonal material.26 The more pronounced change within the P region might be due to several factors. First, because the P region contains approximately eight times as many neurons, there simply are many more retinal axons and terminal arbors within this region. Second, because the axons of M-ganglion cells enter the dorsal surface of the nucleus and traverse the P-layers on their way to the ventral M region,27 atrophy of these fibers also may contribute to a decrease in parvocellular volume. Within the M-layers, the decrease in laminar volume most likely involves a complex combination of axon degeneration, cell shrinkage, and neuronal cell loss (Figs. 4 5 and 8) .
One unexpected result of this study was the relatively constant level of cell loss across animals with different durations of elevated IOP (Fig. 8) . After 2.5 weeks of elevated pressure, the affected M-layers show approximately a 38% loss of neurons, and little change thereafter. A similar pattern was seen for the P-layers; however, the onset of cell loss was delayed approximately 1.5 weeks relative to the M-layers. One possible explanation for this step-like pattern in LGN cell loss is that each region contains subpopulations of neurons with different sensitivities to optic nerve injury. Although the data in Figure 8 may represent an initial loss of the most sensitive neurons, longer durations of elevated IOP may be needed to show the loss of more resistant neurons. That the M-layers of the primate LGN may contain neurons with different sensitivities to axonal injury has been suggested previously,28 and Golgi studies have described at least two types of relay cells in this region of the nucleus.29
An obvious question is, why do LGN neurons degenerate after damage to the optic nerve? In the case of retinal ganglion cell death and glaucoma, pressure-induced damage to the optic nerve has been shown to disrupt axonal transport,9 30 31 which then results in a decrease in the amount of trophic material ganglion cells obtain from their target neurons in the LGN. Because elevation of IOP does not damage LGN neurons or their connections with target neurons in visual cortex directly, it seems likely that neurons in the glaucomatous LGN degenerate primarily because of a decrease in neuronal activity within the retino-geniculo-cortical pathway. LGN neurons may require a minimum level of activity to maintain connections with visual cortex and obtain sufficient amounts of trophic material for their survival. A reduction in neuronal activity may also explain the cellular changes seen within the unaffected layers, a phenomenon not restricted to glaucoma.8 32 Because LGN neurons representing each eye innervate common targets in visual cortex, a reduction in cortical activity that produces a general decrease in cortical trophic levels would have an effect on cells in all layers of the nucleus.
At present, there is good evidence that retinal ganglion cells in the glaucomatous eye die by apoptosis.33 34 Although similar studies have not been conducted in the LGN, transynaptic apoptotic cell death has been described in other systems.35 36 This does not preclude concomitant involvement of necrotic cell death, however, because both necrosis and apoptosis have been demonstrated in the LGN after visual cortex damage37 and in the retina after pressure-induced ischemia38 39 and optic nerve crush.40 Interestingly, neurons undergoing each type of cell death appear to follow a different time course: Neurons that die soon after the insult do so mainly by necrosis, whereas those that die later undergo apoptosis.
Although we cannot address the functional significance of our cellular changes, it is of interest to note that Smith et al.41 reported few abnormalities concerning the functional integrity of LGN neurons or their retinal afferents in monkeys with experimental glaucoma. This result is somewhat surprising, considering the structural abnormalities of ganglion cells in the glaucomatous eye14 and the transneuronal changes described in this study. One possible explanation is that retinal ganglion cells and LGN neurons are capable of maintaining much of their functional integrity, despite significant changes in morphology. Current retinal studies are examining this possibility.
Although many questions remain, these data demonstrate clearly that chronic elevation of IOP has a profound degenerative effect on the primate LGN, a major structure involved in the integration and transfer of visual information. Although our estimates of pressure-induced cell loss suggest that glaucoma has a more pronounced effect on neurons in the M- than in the P-pathway, perhaps the more important message is that in strategies intended to mitigate glaucomatous neuropathy, treatment of the entire central visual pathway, and not the eye alone should be considered.
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Acknowledgements |
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Footnotes |
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Submitted for publication September 1, 1999; revised December 7, 1999; accepted December 16, 1999.
Commercial relationships policy: N.
Corresponding author: Arthur J. Weber, Department of Physiology, B-512 West Fee Hall, Michigan State University, East Lansing, MI 48824. weberar{at}msu.edu
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