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From the Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor.
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Abstract |
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METHODS. P23H heterozygote (lines 1 and 3) and Sprague–Dawley control rats were studied at 4 to 29 weeks by retinal histology, electroretinogram (ERG), and a-wave transduction modeling.
RESULTS. Both line 1 (faster degeneration) and line 3 (slower degeneration) showed progressive rod outer segment (ROS) shortening and outer nuclear layer (ONL) cell loss with age. ERG b-wave maximum amplitude (Vbmax) decreased with age, but b-wave threshold remained constant within each line despite progressive ONL thinning and ROS shortening. The only exception was in line 1 at 29 weeks, which showed a slight threshold change relative to earlier ages. Vamax and a-wave threshold changed more rapidly and were more sensitive than the b-wave in reflecting histologic degeneration. Vamax was linearly proportional to the product of (ROS x ONL) across a two log unit range of data combined from both lines. The photopic b-wave was normal for both lines until the ONL thinned beyond 50%. Phototransduction sensitivity was normal for both lines, and dark-adaptation recovery after bleaching rhodopsin was normal.
CONCLUSIONS. The P23H transgenic rat has a slow rod degeneration with initially normal cone function, consistent with clinical findings of P23H patients. However, the normal bleach recovery and the normal phototransduction sensitivity in this rat model are different from human P23H disease. a-Wave measures were more sensitive than the b-wave for tracking changes. b-Wave threshold was inexplicably poor for tracking degeneration. Although line 1 degenerated faster than line 3, the functional–structural correlates were the same. The tight linear relationship between saturated a-wave amplitude and the product of (ROS x ONL) indicates that the density of cGMP-gated channels per unit ROS plasma membrane area remains constant over a wide range of degenerations.
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Introduction |
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Laboratory studies to rescue photoreceptor cells from degeneration use animal models that mimic human RP. Strategies to slow photoreceptor degeneration include survival-promoting factors,7 retinal transplantation,8 and gene therapy.9 P23H transgenic mice, including the VPP mouse, have been developed and characterized for retinal histopathology and function, and these murine models manifest progressive retinal degeneration similar to that in human adRP.10 11 12 13 However, the tiny mouse eye poses difficulty with surgical manipulations, and this led to the development of the rhodopsin transgenic rat, which has larger eyes. The P23H transgenic rat carries a mutant mouse opsin gene in addition to the endogenous native opsin genes14 15 and undergoes a gradual photoreceptor loss that is generally characteristic of human adRP.3
To use the P23H rhodopsin transgenic rat for rescue studies, we wanted a careful description of the natural history of degeneration against which to judge therapeutic success. The electroretinogram (ERG) provides an important means of tracking degeneration noninvasively; and in these studies, we particularly wanted to correlate ERG changes with the histopathology. Results showed that this P23H transgenic rat has slowly progressive rod dysfunction, with initially normal cone function, consistent in broad outline with clinical findings reported in human P23H adRP patients.3 However, the P23H rat showed some functional differences from human disease in the results of phototransduction modeling and the presence of a normal rate of recovery from bleach. We found that the a-wave was more sensitive than the b-wave for tracking the histopathologic status across a wide range of photoreceptor cell loss in this rat RP model.
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Methods |
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ERG Recording
Animals were dark-adapted for 12 hours and prepared under red dim
light. Animals were anesthetized with a loading dose of xylazine (13
mg/kg intramuscular [IM]) and ketamine (86 mg/kg IM) and then
maintained by slow subcutaneous infusion. Pupils were dilated with
topical 0.1% atropine and 0.1% phenylephrine HCl. Body temperature
was kept at 37°C with a heating pad. ERGs were recorded from both
eyes simultaneously using chlorided silver wire loops on the
corneas, with 1% tetracaine topical anesthesia and a drop of
methylcellulose for corneal hydration. A chloride silver reference
electrode was placed on the sclera 1 mm from the temporal limbus of
each eye. The ground electrode was on the left ear. Responses were
amplified at 10,000 gain at 0.1 to 1000 Hz, filtered to remove 60 Hz
noise, and digitized at a 10-kHz rate. Scotopic ERG responses were
computer-averaged with stimulus intervals of 3 to 60 seconds depending
on intensity, and 20 to 30 photopic responses were averaged with
stimulus intervals of 1 second. ERGs were recorded to Ganzfeld white
(2800°K) 50 msec stimuli with a maximum intensity of 2.2 log candela
[cd]/m2 that was attenuated with
neutral density filters. Photopic ERGs were recorded on a 34
cd/m2 white background. Animals were
light-adapted for 10 minutes before photopic recordings. Threshold
criteria were 10, 20, and 50 µV for the photopic b-wave, scotopic
a-wave, and scotopic b-wave, respectively.
Dark-Adapted b-Wave Recovery after Bleach
Recovery of b-wave amplitude during dark-adaptation was studied in
8-week-old SD control and P23H line 3 rats after a 25-second exposure
to 300 cd/m2 white light, which bleaches
approximately 21% of rhodopsin in the rat retina.16
ERG
responses were recorded in the dark every 5 minutes for 2 hours with
10-µsec flashes of -3.4 log cd-s/m2 (model
PS33; Grass Instruments, Quincy, MA). This flash intensity is quite dim
and elicits a rod-isolated b-wave with essentially no contribution from
the cones17
; flashes every 5 minutes do not desensitize
the response. Responses during recovery were normalized by the
dark-adapted b-wave amplitude to this same stimulus recorded
immediately before the bleach.
Phototransduction Modeling of Saturated a-Waves
Bright flash ERG a-waves were recorded from both eyes
simultaneously with gold wire electrodes to avoid photovoltaic
artifacts. Responses were amplified at 5000 gain from 1 to 1000 Hz and
digitized at 20 kHz. Bright 1-msec photostrobe flashes (model 283;
Vivitar, Santa Monica, CA; color temperature 5500°K) were presented
in a Ganzfeld Bowl, with maximal intensity of 2.1 log
cd-s/m2, which produced a maximal retinal
intensity of 3.57 log scotopic troland (td)-s and attenuated by neutral
density filters with 0.5 log unit steps. Flashes were spaced at 1 to 15
minutes to avoid adapting the a-wave. Bright flash ERGs were recorded
from 4-week-old rats using 5 each of P23H lines 1 and 3 and SD
controls.
The leading edge of the a-wave (P3) was fitted with the Hood
and Birch version18
of the Lamb and Pugh
model19
(see Eq. 1
below), with a-wave termination
chosen as just before the upturn of the a-wave or 15 msec after flash
onset. The effective time delay (Teff)
between flash and a-wave onset was determined by fitting a straight
line to the baseline data, and to 1 msec of data after the signal
deviates three standard deviations beyond the baseline
noise20
at the highest intensity.
Teff is set as the point where the two
lines intersect and is fixed for all lesser intensities. To estimate
Teff independent of observer bias,
Rmax was set equal to the value of the
a-wave elicited by the brightest flash intensity. The sensitivity
(S) was the only parameter allowed to vary and was fit to
individual traces to observe the changes in S with
intensity.
 | (1) |
Histology
Rats were killed with sodium pentobarbital overdose 1 day after
ERG recordings. Eyes were enucleated and fixed overnight at 4°C in
2% paraformaldehyde and 2.5% glutaraldehyde in 0.1 M cacodylate
buffer. Eyes were postfixed in 1% osmium for 1 hour. Epon-embedded
tissue was sectioned 1-µm thick along the vertical meridian through
the optic nerve and stained with toluidine blue for light microscopy.
Column cell counts of outer nuclear layer (ONL) thickness and the
length of the rod outer segment (ROS) were determined every 400 µm
across both the superior and inferior hemispheres, and the resulting
numbers were averaged for each retina to obtain a measure of cellular
changes across the entire retina. This provided a whole-retina
measurement for comparison with Ganzfeld ERG function.
Statistical Analysis
The two-tailed Student’s t-test was used to compare
paired data from age-matched control and transgenic rats. Data across
ages were analyzed with the Kruskal-Wallis test, which is a form of
ANOVA that does not presume any specific distribution.21
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Results |
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ROS length was correlated with ONL width across both lines 1 and 3 (R = 0.93, Fig. 2B ). In line 1 at 29 weeks of age, ROS length deviated downward from the regression line because end-stage disease had thinned the ONL to less than a two cell width. This suggests that photoreceptor cells can survive for a short time even with very little ROS. An example of this is found in the rhodopsin knockout mouse,22 which initially produces a full complement of rod cells that fail to elaborate ROS but survive for many weeks before ultimately dying by 11 weeks.
Scotopic ERG
The dark-adapted ERG was characterized by three measures:
threshold for criterion amplitude responses, rod-mediated scotopic
maximum amplitude (Vmax), and intensity to elicit
one-half maximum amplitude (also termed the "k" value, or
sensitivity) (Fig. 3
and Table 1 ). For dark-adapted recordings, the maximum rod b-wave
(Vbmax) without cone contamination occurs just
before the dip of the intensity-response function.17
This
dip is easily seen in line 3 animals but is difficult to judge in line
1 rats because of an a-wave amplitude loss, and
Vbmax was taken as the b-wave amplitude on the
plateau just before the second increase. Vbmax
was significantly smaller for the transgenic rats, except for
4-week-old line 3 animals, compared with SD controls (P < 0.01) and decreased progressively with age in both lines
(P < 0.01). In line 1 Vbmax
decreased rapidly between 15 and 29 weeks, as the ONL is thinned to
below 2 cell width.
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Because a-wave thresholds increased with age, it was surprising that b-wave thresholds remained virtually constant within each line for all but the end-stage condition of line 1 at 29 weeks (Fig. 3) . At 4 weeks of age, b-wave threshold was significantly elevated for both line 1 and line 3 compared with the SD controls (P < 0.01). However, thereafter for each line, thresholds changed minimally with age for either line (0.15 log unit for line 3 at 4 to 29 weeks, and 0.10 log unit for line 1 at 4 to 15 weeks) and were comparable to the threshold variation with aging found for the SD controls (0.08 log unit, 4 to 29 weeks). Testing for non-zero slope by linear regression of b-wave threshold across ages 4 to 29 weeks gave P = 0.12 for all animals in line 1 and P = 0.21 for all animals in line 3, indicating that threshold was essentially static with age. This suggests that some compensatory mechanism was acting on the b-wave to stabilize threshold despite the progressive photoreceptor loss. The sole exception was in line 1, in which the threshold increased by 0.3 log unit between 15 to 29 weeks; these advanced animals had massive loss of rod cells and ROS shortening by this age and showed an overall shift in the V-log I response function (Fig. 3C) .
Correlations between Retinal Function and Histopathology
Vamax and Vbmax are
frequently used to correlate with ONL cell counts as an indication of
the stage of retinal degeneration. Figure 4
shows data from lines 1 and 3 plotted together. The change in log
Vmax of both the a- and b-waves was proportional
to ONL cell loss (a-wave, R = 0.94; b-wave,
R = 0.89; Fig. 4
), but Vamax
slope was approximately double that of Vbmax,
indicating that Vamax is more sensitive for
detecting photoreceptor cell loss. Note that in end-stage disease the
lowest two points deviate downward from these straight lines, as
expected, because when all cells are lost, both
Vamax and Vbmax must head
toward "zero." What seems remarkable is the good fit of these
regression lines across data pooled from both lines 1 and 3 comprising
a more than 80% range of cell loss. This suggests that the
degeneration process is similar across these two lines for all but
end-stage ONL cell loss.
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In a previous study, saturated amplitude of fast PIII was proportional to ROS length for albino rats reared under a different lighting intensity.23 In that study, ROS length was manipulated through the process of photostasis to two light-rearing intensities. The P23H rhodopsin mutant animals provide an opportunity to extend this observation to include the case of cell loss in addition to ROS shortening. A-wave saturation occurs at the flash intensity sufficient to close all cGMP-gated channels and to completely interrupt the rod dark-current. If one assumes that channel density per unit area of ROS plasma membrane remains constant despite a change in ROS length, then the total dark-current per rod would be proportional to ROS length, as found by Reiser et al.23 However, in the P23H rat, total retinal photocurrent will also be proportional to the number of rod cells remaining. Consequently, for the P23H rat, the maximum photocurrent change on complete channel closure with a saturating ERG flash would be proportional to the product of ROS length and ONL cell count (ROS x ONL). Figure 5A provides support for this idea by the tight linear correlation between Vamax and ROS x ONL across both lines 1 and 3 (R = 0.96). Note that, like the Ganzfeld ERG, the histology represents a global retinal assessment, because ROS and ONL were averaged across the entire retina. These data are well fitted across a 100-fold range for both Vamax and ROS x ONL, and the line regresses to zero a-wave voltage for zero ROS x ONL. This suggests that ROS plasma membrane channel density is maintained during degeneration. Neither ROS nor ONL alone gives a direct relationship of Vamax. ONL is related to the logarithm of Vamax (Fig. 4) and consequently deviates considerably from direct proportionality. The same is true for ROS versus Vamax (not shown but as one might anticipate from the linear relationship of ROS with ONL shown in Fig. 2B ).
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Phototransduction a-Wave Modeling
Figure 6A
shows ERG responses to a bright flash, averaged from 5 animals of line
1 and 5 SD controls at 4 weeks of age. The a-wave amplitude of the P23H
rat line 1 was approximately 25% of the SD control at 4 weeks of age,
but in this figure it was normalized to the SD control a-wave maximum.
The b-wave amplitude relative to the a-wave was considerably larger for
the transgenic rats compared with SD controls (P <
0.01), which is consistent with the evidence shown in Figure 3
that the
b-wave amplitude was more preserved than the a-wave in this model. The
peak implicit time of the transgenic a-wave was approximately 1 msec
faster than the control (Fig. 6A
, inset), indicating greater
sensitivity for the P23H response.25
The same observation
was made by formal fitting of the a-wave with the phototransduction
model (see Eq. 1
).19
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Values of S were
averaged across five animals in each group and were plotted as a
function of stimulus intensity (Fig. 6B)
. Rmax of
the a-wave was reduced to 25% and 88% of SD controls for lines 1 and
3, respectively, at 4 weeks, roughly proportional to ROS x ONL,
which were 35% and 77% of the control value for these lines at this
age. The log S values for transgenic rats was higher across
the entire stimulus intensity range compared with SD control rats
despite the considerable Rmax reduction.
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Discussion |
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Line 3 degenerated comparatively slowly out to 29 weeks, as assessed by histology and the ERG. Even in line 1, with massive cell loss by one-half year age, these animals retained more than 20% of dark-adapted b-wave amplitude at 29 weeks of age. Rats usually do not live beyond 2 years, and this functional retention at one-half year suggests that these animals retain vision for a relatively long period of their lives. P23H patients have significantly better visual acuity and larger ERG amplitudes than adRP from other mutations and may retain useful vision to approximately 70 years of age.3
ERG rod function was impaired before photopic cone function, which is consistent with clinical P23H patients.3 The photopic ERG in line 1 rats was normal at 4 weeks and began to decline by 8 weeks of age, when the ONL was thinned by one half, suggesting that loss of considerable number of rods can occur before significant cone degeneration in this rat model. Regional distribution of retinal degeneration is seen in human P23H disease,29 30 probably associated at least in part with geographic differences of the relative rod/cone ratio in the human retina. In the P23H rat the degeneration is relatively uniform across the retina, and no significant difference was found between superior and inferior hemispheres in remaining ONL cells at any age of 4 to 29 weeks of age.
The rod b-wave of the P23H rat recovered normally after a bleaching light exposure, unlike human P23H disease in which dark-adaptation is markedly slowed by as much as twice normal.31 This is also dissimilar to the VPP mouse with a P23H rhodopsin mutation which shows slow rod b-wave recovery from bleach.12 P23H opsin is partially misfolded but correctly forms the pocket for 11-cis-retinal.32 The ERG data in the P23H rat indicates that reconstituting of rhodopsin after bleach appears to be normal.
P23H rat also differs from human P23H disease in transduction sensitivity. The P23H rats showed no decrease in phototransduction sensitivity, and this was also normal in the VPP mice with a P23H mutation.13 However, reduced sensitivity was reported for human P23H disease,33 with S decreased by 0.5 to 0.9 log unit in three patients, including two young individuals of 18 and 27 years of age who retained good visual field diameter. These patients had severely impaired rod and cone function; however, with Kb (rod b-wave semisaturation constant) elevated by more than one log unit, which is considerably more than the 0.4 log unit elevation of even our most affected P23H line 1 rats at the 29-week age. Consequently, one may suspect that these patients had advanced retinal histopathologic changes that contributed to the decreased phototransduction sensitivity rather than resulting from molecular changes of opsin.
ERG Changes in P23H Rat Degeneration
Sensitivity of the a-wave (determined as the intensity for
one-half Vamax) of SD controls and line 3 animals
at all ages was approximately 1.0 log cd/m2
(Table 1)
. Even at 29 weeks of age when the line 3 animals produced
a-waves only one half the amplitude of controls and had histologic ROS
shortening and approximately 50% ONL cell loss, the a-wave sensitivity
was approximately 0.1 log unit different from that of controls.
Similarly, for line 1 animals with severe degeneration and only 10% of
normal a-wave amplitude by 29 weeks, very little change of a-wave
sensitivity was found; the change was less than 0.2 log unit at 29
weeks compared with both 4-week-old line 1 animals and 29-week-old
control animals. This indicates that the input–output relationship of
the rod cell in converting incident light to ROS membrane
photovoltage/photocurrent change remains essentially constant despite
degeneration. This is further confirmation of the findings from formal
phototransduction a-wave modeling, in which log S values
were preserved in line 1 despite a 75% a-wave amplitude loss.
The b-wave was preserved relatively better than the a-wave as the retinal degeneration progressed. This suggests that enhanced gain may occur at the photoreceptors or beyond to compensate for decreasing photic input as the ROS shortens and the rod cell counts decrease during degeneration. However, there appears to be a limit to the compensation, because the scotopic maximum b-wave amplitude was considerably decreased by 29 weeks in P23H line 1 rats with advanced degeneration to 2 ONL rows and less.
The mechanism of this phenomenon remains uncertain. One possible explanation is that the wide receptive field of the bipolar cell provides buffering against loss of photoreceptors. Bipolar cells receive input from as many as 45 rods,34 and a maximal bipolar response might result from signaling by fewer than all these rods. In such case, the maximal b-wave response could be reached in degeneration even though the pooled a-wave response of rod photocurrents was decreased. However, with very advanced degeneration, the rod bipolar cell may lose input from enough rods to cause the scotopic b-wave amplitude to decline.
A second possibility is that synaptic plasticity may allow some degree of compensation of retinal signaling as rods are lost. In the peripheral nervous system, loss of presynaptic elements from one motor neuron during development causes an increase in signaling of the remaining elements.35 Synaptic rearrangement may also take place in the adult central nervous system,36 and growth factors such as transforming growth factor-ß can strengthen synaptic signaling.37 Furthermore, in the retina the rod-to-bipolar cell synapse shows signaling plasticity during diurnal light cycling of the day/night rhythm.38 This suggests that synaptic remodeling could occur in the P23H rat retina during photoreceptor degeneration. Evidence of this would require electron microscopy rather than ERG methodology.
The scotopic b-wave near its threshold was surprisingly preserved and remained nearly constant in each line throughout the 29-week study, except for the 29-week line 1 rats with quite advanced ONL and ROS degeneration. If dimmer stimuli activate rhodopsin and close cGMP-gated channels preferentially at the base rather than the tip of ROS,39 b-wave threshold might be relatively protected against modest ROS shortening.
The RCS rat also shows relative preservation of post-photoreceptoral ERG responses during retinal degeneration,40 particularly for the scotopic threshold response (STR), which reflects amacrine cell activity.41 Relative sparing of STR, despite progressive loss of photoreceptors, is also reported in light-damaged rats.42 This is similar to the P23H rat, in which the oscillatory potentials (OPs) in Figure 6A were well preserved for these line 1 animals with a 75% reduction of the a-wave. Although we did not systematically analyze the OPs in this study, this suggests that other postreceptoral potentials, in addition to the b-wave, are preserved relatively better than the a-wave at this stage of P23H disease.
Correlation between the ERG and Histopathology
This study sought to identify ERG parameters that were sensitive
to the extent of degeneration, for use in studying efficacy of
photoreceptor rescue strategies. The saturated a-wave amplitude
correlated directly with the product of (ROS x ONL) across nearly
two log units of a-wave amplitude and cellular structural changes, in
data pooled across lines 1 and 3. The product (ROS x ONL) should
reflect the total remaining ROS plasma membrane area, which contains
the cGMP-gated channel. This extends the observations of Reiser et
al.23
by including cell loss in addition to a wide range
of ROS shortening and adds to the conclusion that the saturated a-wave
amplitude directly reflects rod photocurrent. Both the a-wave amplitude
and the photoreceptor structural change and loss regressed to zero
simultaneously. Consequently, the a-wave provides an excellent
noninvasive measure for tracking progression of photoreceptor disease
in these P23H rats. If the correlation of a-wave with (ROS x ONL)
is borne out in other animal models of retinal degeneration, this may
provide a useful measure to judge the extent of rod degeneration in
human RP disease.
a-Wave modeling gave normal phototransduction sensitivity for transgenic P23H rats despite ROS shortening and the outright loss of photoreceptors. Furthermore, the tight linear correlation of maximum a-wave amplitude with (ROS x ONL) indicates that plasma membrane density of cGMP-gated channels seems to remain constant despite ROS shortening. These findings suggest that the remaining photoreceptors in the P23H rat retain good function despite having short ROSs. b-Wave maximum amplitude and threshold were both preserved better than those of the a-wave in advanced disease, indicating that a-wave measures are preferable for tracking degeneration across the entire disease spectrum.
The P23H rat ERG was slightly different from light damage rat for which a log–linear relationship was found between ONL cell counts and b-wave threshold, with a slope of 0.3 log unit threshold elevation per ONL cell-width loss.42 Several factors may contribute to this. Especially in mild light damage, the STR becomes quite large42 and reduces the b-wave amplitude and impairs b-wave threshold. The P23H rat does not have an exaggerated STR (data not shown).
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Summary |
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Acknowledgements |
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Footnotes |
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Submitted for publication February 7, 2000; revised April 14, 2000; accepted April 26, 2000.
Commercial relationships policy: N.
Corresponding author: Paul A. Sieving, Center for Retinal and Macular Degeneration, W. K. Kellogg Eye Center, University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105. psieving{at}umich.edu
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