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1 From the Departments of Ophthalmology and Visual Sciences, 2 Anatomic Sciences and Neurobiology, and 3 Psychological and Brain Sciences, University of Louisville, Kentucky.
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Abstract |
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METHODS. Sheets of fetal retina with RPE were transplanted into the subretinal space of Royal College of Surgeons (RCS) rats at 37 to 69 days of age. Sixty-three days to 10 months after transplantation, multiunit visual responses were recorded in the superior colliculus (SC) of transplanted rats, age-matched untransplanted rats, and rats with sham surgery.
RESULTS. In 19 of 29 RCS rats with transplants, visually evoked responses were recorded from and restricted to a small area of the SC that corresponds topographically to the portion of the retina in which the transplant was placed. Outside of this area, no visual responses were evoked. Visually evoked responses were never recorded in age-matched, nontransplanted RCS rats. Visually evoked responses were recorded in 6 of 13 RCS rats with sham surgery, but these responses were significantly different from responses in rats with transplants.
CONCLUSIONS. These results demonstrate that this transplantation technique restores visually evoked responses in the brain. Although the underlying mechanism is unknown, we propose that the central visual response results from increased synaptic efficacy within the host retina. If it can be established that functional connections between the transplant and the host retina produce the effect, then it would indicate that the technique could be explored as a therapeutic strategy in some diseases of retinal degeneration.
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The Royal College of Surgeons (RCS) rat is one model of retinal degeneration and has been used extensively to assess treatments for photoreceptor degeneration. Injection of bFGF12 and transplants of various tissues, such as dissociated retinal pigment epithelium (RPE) cells,13 14 iris pigment epithelial cells,15 and Schwann cells,16 delay degeneration of photoreceptors if transplantation is performed before postnatal day 28 (P28). A similar delay results from sham surgery.17 18 19 However, sham surgery and these generic transplantation strategies, which rely on the release of trophic factors, have no therapeutic effect if the surgery is performed after P38.20 Thus, when photoreceptor degeneration is advanced, therapies that rely on trophic support appear to be of limited value because they cannot replace the degenerated cells.
Whether retinal transplantation can be used as a therapeutic approach in photoreceptor degeneration depends on the ability of the transplant to make functional connections that are capable of evoking visual responses in the host. Several studies provide data that suggest that functional connections may form after transplantation. Embryonic retinas transplanted to the superior colliculus (SC) of newborn hosts make functional connections with the SC and drive a pupillary reflex.21 22 23 24 Retinal aggregate transplants, dissected from the host eye in which they matured, drive a local light-evoked electroretinogram in vitro.25 Injections of dissociated fetal retinal cells into the subretinal space of light-damaged rats appear to mediate a visually evoked behavior.26 Postnatal photoreceptor sheets transplanted into the eye of light-damaged rats may result in visually evoked potentials (VEPs) in the cortex, although interpretation of these data is not straightforward because the age at which transplantations were performed was not reported.27 In a mouse model of retinal degeneration, rd, implantation of retinal microaggregates affects a light–dark behavior preference.28 Taken together, these results suggest a beneficial effect of transplantation on restoration of vision. However, none of these studies directly demonstrates that either a physiologically significant connection arises between the transplant and the existing circuitry of the host retina or that visual responses are retinotopically localized in a brain structure that receives direct input from retinal ganglion cells.
Aramant and Seiler29 30 31 have developed a retinal transplantation technique in which an intact sheet of fetal retina is transplanted with or without its RPE into a degenerated host retina. The transplanted fetal retina develops a normal lamination pattern and, several components of the normal visual transduction cascade are modulated by light in its photoreceptors.31 Processes arise from cells in the transplant and appear to cross into the host retina,32 and cells in the transplant can be transsynaptically labeled by retrogradely transported virus injected into the SC.33
To determine whether retina/RPE transplantation results in visually evoked responses in a central visual structure, we placed transplants in RCS rats 1.2 to 2.1 months of age, by which time their photoreceptors are irreversibly damaged20 and recorded multiunit visually evoked responses in the SC. With this approach, the site of each visually responsive area could be localized on the topographic map of the SC34 and compared with the position of the transplant in the retina. The data presented here demonstrate that cotransplantation of fetal retina/RPE restores visually evoked postsynaptic responses in the SC of the RCS rat. These responses are elicited only in regions of the SC that topographically match the retinal area in which the transplant is placed. Visual responses also could be evoked in the SC of rats with sham surgery, although these responses are both quantitatively and qualitatively different from those driven by the transplant. Thus, our results show that the presence of the transplants produces an effect on visual activity. If this activity is directly related to visual perception, then transplantation of sheets of retina/RPE could be useful as a therapeutic approach to maintain or restore light perception in patients with retinal degenerative diseases.
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Methods |
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Transplant Tissue Preparation
The procedure has been described in detail
elsewhere.29
30
Donor retinal tissue was obtained from
embryonic day (E)19 to E20, pigmented Long-Evans rat fetuses. Donor
eyes were incubated in dispase (Collaborative Biomedical Products,
Bedford, MA), and the retina with its attached RPE was dissected free
of surrounding tissues and embedded in 0.4% MVG alginate (Pronova,
Oslo, Norway). Some control rats received transplants of fetal cortex.
For this condition, donor cortex was removed from the same aged embryos
and cut into thin sections by hand.
Transplantation Procedure
In anesthetized rats, a small incision (
1 mm) was cut behind
the pars plana of the host eye, and the transplant (either retina or
cortex) was placed into the subretinal space, in the superior nasal
quadrant of the host, using a custom-made implantation tool.
Sham Surgery
The surgical procedures for the sham surgeries were identical
with those used in transplantation with the exception that the tool did
not contain any tissue when it was placed into the subretinal space.
Experimental Animals
Electrophysiological recordings were made in the SC of 29 albino
RCS rats with retina/RPE transplants. Recordings also were made in four
groups of age-matched controls: 12 normal rats (8 pigmented Long-Evans
rats and 4 albino Sprague–Dawley); 6 nontransplanted albino RCS rats;
13 RCS rats with sham surgery and 3 RCS rats with fetal occipital
cortex transplants (Table 1)
. Transplanted rats were 3.6 to 10.7 months of age at the time
of recording, which was 1.4 to 8.4 months after transplantation.
Control rats were 2 to 12.7 months of age. A subset of these rats (6
with sham surgery and 2 with retinal transplants) was recorded with the
experimenters blind to their experimental group.
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Electrophysiology
Anesthesia was induced with 4% halothane mixed with room air, followed
by an intraperitoneal injection of a mixture of xylazine/ketamine (37.5
mg/kg ketamine and 5 mg/kg xylazine) in sterile saline. A tracheostomy
was performed to enable artificial ventilation. The femoral vein was
cannulated for drug and saline infusions. Blood pressure was monitored
via a cannula in the femoral artery, which was attached to a pressure
transducer (model BP-1; World Precision Instruments [WPI], Sarasota,
FL). During the recordings, the rats were paralyzed by a combination of
pancuronium bromide (0.1 mg/kg/h) and curare (0.01 mg/kg/h) in saline
(0.8 ml/h) and artificially ventilated with 1.0% to 2.0% halothane in
40% oxygen/60% nitrous oxide. The level of halothane was adjusted to
maintain blood pressure between 60 and 80 mm Hg. The end-tidal
CO2 level was maintained at 2.8% to 3.1%. The pupils were
dilated by topical application of 1% atropine sulfate, and the corneas
were protected with artificial tear ointment. Each rat was mounted in a
stereotaxic apparatus, a parietal craniotomy was performed, and the SC
was visualized by removing the overlying cortex by suction.
Multiunit visual responses were recorded extracellularly from the
superficial laminae of the SC using commercially available metal
electrodes (WPI) whose resistances were between 1.0 and 1.5 M
. The
electrode was positioned at the surface of the SC using stereotaxic
coordinates with references to lambda and the edges of the exposed SC.
In each animal, multiple electrode penetrations were performed, and the
electrode was advanced through the SC using a hydraulic microdrive
(Kopf Instruments, Tujunga, CA). The first penetration was positioned
at the caudal end of the SC in a location that matched the topographic
area of the retina containing the transplant. Subsequent penetrations
moved rostrally by 200-µm steps until the anterior pole of the SC was
reached. A second, parallel row of penetrations was positioned 200 µm
laterally and moved from rostral to caudal. At each position, the
electrode was lowered 100 µm beyond its point of contact with the
surface of the SC, 16 to 32 presentations of a full-field visual
stimulus were performed, and the responses were recorded using a
digital data acquisition system (Powerlab; AD Instruments, Mountain
View, CA). The electrode was then either lowered through the SC in
50-µm steps, and visual responses were noted or it was moved to
continue to map the extent of the visually responsive area. Multiunit
signals were recorded, amplified, and filtered from 200 and 16,000 Hz
(Fintronics Bioamplifier, Orange, CT), displayed on a Tektronics model
5103 storage oscilloscope (Beaverton, OR), and monitored via an audio
monitor. Blank trials, in which the photostimulator was blocked by a
light-tight cover also were recorded to establish the baseline activity
level at each site. On penetrations where no visual response could be
elicited, activity was sampled up to a depth of 900 µm.
A full-field strobe flash (1300 cd/m2) was delivered to the eye using a photostimulator (model PS 22 Photic stimulator; Grass, West Warwick, RI), positioned 30 cm in front of the rat’s eye. An interstimulus interval of 5 seconds was used.
Input from two channels was simultaneously acquired: one channel represented the external trigger from the photostimulator and the second the extracellular visual signal elicited by the stimulus. A pretrigger, 100 msec before the onset of the light flash, initiated each 500-msec sweep. The onset of the visual response was defined as the point at which a clear, prolonged (>20 msec) increase in activity could be measured above the background activity. The latency of the response for each sweep was measured by positioning two cursors, one at the onset of the stimulus artifact and the second at the onset of the visual response. Mean latencies and SDs were computed both for each recording site, for all sites within each animal, and for all animals within each group. Peak response amplitudes were measured from the averaged sweeps at each visually responsive position in each animal. The peak response was defined as the largest excursion peak to peak in this response.
Histology
At the end of each recording experiment animals were perfused
transcardially with saline followed by fixative. The eyes were removed,
and the eyecups were postfixed and subsequently either embedded in epon
or paraffin or frozen in Tissue-Tek. Transverse sections of the retina
were cut, mounted onto slides, and stained with either
hematoxylin–eosin or toluidine blue. A series of sections through the
full extent of the transplant were evaluated by light microscopy.
The presence of S-antigen immunoreactivity was analyzed in retinal paraffin sections from 12 rats that received retinal transplants (n = 10 rats with visual responses and n = 2 rats without visual responses), 8 rats that received sham surgery and 3 RCS rats without transplants (Table 1) . Deparaffinized sections were washed with phosphate-buffered saline (PBS) and incubated for 30 minutes in 20% horse serum. The sections then were incubated with a monoclonal antibody against S-antigen (clone A9C6; gift of Larry A. Donoso35 ) at a dilution of 1:20,000 overnight at 4°C. After several washes with PBS, the binding of the primary antibody was detected using the Vector Elite ABC kit for mouse antibodies (Vector Laboratories, Burlingame, CA).
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Results |
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Normal Controls
Normal pigmented rats represent the control for the transplanted
retina. In these rats, both single and multiunit visual responses were
recorded in response to a full-field flash (Fig. 1A)
and receptive fields were mapped onto a tangent screen, using a hand
held lamp (Keeler, Broomall, PA). These data (not shown) provided our
stereotaxic map and were essentially identical with published maps of
the rat SC. Unpigmented rats represent the control for the RCS retina.
There was no difference in the responses in the SC of the pigmented and
unpigmented controls (see Fig. 4
).
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Response Onset Latency
The latency of the onset of each visual response was determined
for all groups of rats. Figure 4
plots the onset latency for individual
recording sites as a function of its peak amplitude for normal
pigmented and unpigmented controls (filled and open diamonds,
respectively); transplanted rats (filled circles), and sham controls
(open triangles). The latencies from normal controls were taken from
sites in an area of the SC comparable to that in transplanted rats. In
normal controls, onset latency ranged from 24 to 52 ms with a mean ± SD of 35 ± 8 ms, which is within the range of previously
published data.36
37
In contrast, onset latency in
transplanted rats ranged from 67 to 103 ms, with a mean of 79 ±
11 ms and showed no overlap with normal controls. Onset latency in sham
controls ranged from 66 to 166 ms with a mean of 118 ± 37 ms.
Mean latencies also were computed for each animal, and an overall mean
was computed. These values are similar to those computed over all
cells. An ANOVA was performed and showed a significant group effect
(F = 79.3; P < 0.001), and a post hoc
test (Bonferroni) showed a significant difference between the rats with
transplants and the sham controls (P < 0.001).
Peak Response
For each normal, transplant, and sham control rat, the peak
amplitude of each response was determined and is plotted in Figure 4
.
In normal controls, peak responses ranged from 98.5 to 170 mV with a
mean of 130 ± 19 mV. Peak responses in transplanted rats ranged
from 75 to 156 mV with a mean of 108 ± 22 mV and in sham controls
ranged from 66 to 130 mV with a mean of 80 ± 20 mV. An ANOVA
showed a significant group effect (F = 18.2;
P < 0.001), and a post hoc test (Bonferroni) showed
that there was a significant difference between the rats with
transplants and the sham controls (P = 0.002).
Consistency of Response Onset Latency
We assessed the consistency of the onset latency of the visual
response by measuring the difference between its shortest and longest
response latency within a given sequence of 16 stimulus presentations.
In normal controls, the mean difference was 9 ± 3 ms. In rats
with transplants, this difference was 14 ± 5 ms and in the sham
controls the difference was 24 ± 4 ms. An ANOVA was performed, a
significant group effect found (F = 30.1
P < 0.001), and a post hoc test (Bonferroni) showed a
significant difference between the rats with transplants and the sham
controls (P < 0.001).
Histologic Evaluation
Qualitative histologic evaluations of transverse retina sections
were performed for all RCS rats with transplants, for 10 sham controls
and for 2 cortical transplant controls. Transplants were examined for
laminar and overall morphologic organization and whether their
photoreceptors had developed outer segments. In addition, both the host
retina of eyes with transplants and RCS control retinas were examined
for the presence and number of S-antigen–positive cells, indicating
the continued presence of host photoreceptor cells.
The retinal transplants exhibited a range of organizations that varied from well laminated to transplants containing rosettes (Figs. 5A 5B 5C) . In general, the majority of animals with transplants that elicited a visual response maintained a normal laminar morphology that contained all cellular and synaptic layers. Cell bodies in the outer nuclear layer (ONL) of the transplants had characteristic photoreceptor morphology, although, their outer segments tended to be short or absent (Figs. 5B 5C) . Further, the inner retina of the host adjoining the transplant did not differ morphologically from the inner retina outside the transplant area and, in general, appeared intact (Fig. 5D) . No defined photoreceptor layer could be found in the retinas of any of the controls (i.e., untransplanted, sham surgery, and cortical transplanted retinas), although scattered cells with morphologic characteristics of cones could be found. The density of S-antigen–reactive cells was examined in transverse sections of seven retinas with transplants and revealed no obvious differences in the density of cells (presumably residual cones) in the host retina inside versus outside the transplant area (Figs. 6A 6B) . In addition, no differences in the density of S-antigen–immunoreactive cells were observed in any of the RCS controls. In contrast, the transplants had large areas of immunoreactive photoreceptors in their outer nuclear layers.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In contrast to the rats with retinal/RPE transplants that showed visually evoked activity, in the other 34% we found no visual activity. The reason for this difference within our rats with transplants is unknown. As in previous studies,29 30 the rats studied here, with and without visual activity, exhibited a range of morphologic organization, which varied from well laminated to those containing rosettes. In the majority of the retina/RPE transplanted rats, the transplants consisted of a normal lamination pattern and included an ONL with photoreceptors. In some, the photoreceptors also had outer segments. In the host retina there was no defined ONL, although lamination in the inner retina appeared intact.38 The morphology of the inner retina of all the RCS rats, with and without transplants, with sham surgery and with fetal cortex transplants also was similar. A qualitative examination using S-antigen immunohistochemistry showed no differences in the numbers of positive cells in the host retina adjoining and outside the transplant area. Similarly, no obvious differences in the number of positive cells were seen across the three groups of RCS controls.
The presence of visual activity in some of our sham controls raises issues regarding the mechanisms underlying the visually evoked responses in the SC of transplanted rats. A key question is whether the presence of the transplant maintains already existing connections in the host by means of a trophic factor or whether the transplant restores function by formation of new synapses with the host. The presence of visually evoked responses in the sham controls suggests that surgical intervention, via trophic factor release, can maintain visual responses in the SC. Previous transplantation studies also have shown that surgery itself effects the rate of photoreceptor degeneration or loss of visual function.17 18 This effect of surgical intervention is probably related to the induction of trophic factor expression.39 In addition, both in vitro40 and in vivo14 16 28 41 42 studies indicate that RPE, Schwann cell, and dissociated rod photoreceptor transplants provide trophic factors that delay or arrest the degeneration of host photoreceptors or of visual function. The differences that we observe in both the quantitative and qualitative aspects of the visual responses between the sham controls and rats with retinal transplants suggest that the presence of functional connections between the transplant and the host retina or a factor released from the transplant is responsible for the more robust visual responses. Li and Turner20 showed that the timing of RPE transplantation into RCS rats is a critical factor in delaying the normal course of photoreceptor degeneration. After 38 days of age, RPE transplantation had no effect. Our RCS rats received fetal retina/RPE transplants at 37 to 69 days of age. Therefore, it is unlikely that the response in the SC of the transplanted rats is a simple delay of degeneration in the host related to the presence of the transplant. In addition, in our transplantation model this effect is not reflected in host photoreceptor salvage, again suggesting restoration via an increase in synaptic efficacy of the host circuitry. Thus, the visual responses in the SC are most likely to result from functional interactions between the transplant and existing host circuitry. This hypothesis is supported further by the observation that cells in the transplant are labeled after injections of a retrogradely and transynaptically transported pseudorabies virus43 into the visually responsive area of the SC of transplanted rats.33 The existence of physical connections between a retinal transplant and a normal host retina also has been demonstrated in a rabbit model.44 An alternative explanation for this result is that the transplants send axons through the host optic nerve directly to the SC. The former explanation, however, is more likely for several reasons. First, the visual response in the SC in our transplanted rats is topographically organized. In contrast, projections to the SC from either fetal retina transplanted to the brain45 or from retinal ganglion cell axons regenerating through a peripheral nerve graft to the SC are not topographically organized.46 47 48 Second, the response properties that we record in the SC of transplanted rats, while significantly different from normal rats are considerably more robust than the responses in the sham controls. Taken together these data provide stronger support for the hypothesis that visual activity in the SC is restored as a result of the presence of the retinal transplant and its connections to the host retina, rather than a simple trophic effect. Another explanation for the restored response is a release of excitatory neurotransmitter from the transplant that stimulates cells in the host extrasynaptically. We believe this scenario is unlikely because the neurotransmitter reuptake system in the transplant should remove the transmitter before it can diffuse to the host retina. If the reuptake system was defective, then transmitter release would produce a prolonged excitatory response in both the transplant and the host retina, which should produce excitotoxicity and retinal degeneration. We have not observed either lengthened visual responses in transplanted rats or any nonspecific degeneration.
The presence of the retinal transplant in the eye causes the restoration of the visual responses in the SC either by direct synaptic connections with the host retina or via specific retinal trophic factors that enhance remodeling of the host circuitry or a combination of the two. This could occur by a mechanism similar to that shown in two other models of retinal degeneration.7 8 At this point, our data support the hypothesis that the visual responsiveness results from an increase in synaptic efficacy due to connections from the transplant to the host. However, these data cannot definitively prove that only one mechanism is responsible.
To overcome the complication of the effect of surgical intervention in the RCS rats, we are currently investigating the use of another model of retinal degeneration, the S334-ter line 3 transgenic rat for use in this transplantation paradigm. In this model, the degeneration results from the photoreceptor-specific expression of a truncated form of human rhodopsin,49 50 rather than the RPE defect in the RCS rat. Preliminary data indicate that in S334-ter line 3 transgenic rats with transplants visual responses similar to those reported here are seen, but sham surgery does not result in any visually evoked responses in the SC in these rats.51
Although we have demonstrated that RCS rats with retina/RPE transplants show significantly better responses in the SC than in rats with sham surgery, we cannot predict the level of visual function that will be associated with these responses. It is likely that the increased responsiveness found in the animals with transplants will be reflected in their heightened ability to discriminate light and dark over that found in RCS rats either without transplants or with sham surgery. Should this prove to be the case, retinal transplantation could increase light perception in individuals with advanced photoreceptor degeneration, which could significantly improve their quality of life.
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Acknowledgements |
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Footnotes |
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Submitted for publication March 30, 2000; revised July 26, 2000 and January 30, 2001; accepted February 13, 2001.
Commercial relationships policy: P (RBA, MJS); N (all others).
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. 
1734 solely to indicate this fact.
Corresponding author: Maureen A. McCall, Department of Psychological and Brain Sciences, University of Louisville, Louisville, KY 40292. mo.mccall{at}louisville.edu
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4 months of age; no visual responses were recorded from any location
in the SC. In addition, no visual responses were recorded in the SC of
any of the RCS rats with fetal cortex transplants (data not shown).
(C) In the majority of the rats with sham surgery, no visual
responses were recorded from any site in the SC. Traces 1
and 2: individual sweeps from visually unresponsive
locations in two rats. In 6 of 13 sham surgery controls, long-latency,
weak visual responses were recorded; trace 3: individual
sweep of a response and (mean) the average visual response from that
location. Control: for each recording site, responses were recorded
with the light source covered. No visual responses were elicited in
this condition, which indicates that all other responses originate in
the retina.
; n = 12 sites). Data from
topographically matched areas in 8 normal, pigmented (
;
n = 18) and 4 normal, unpigmented (
;
n = 16) controls. In three transplanted rats
quantitative data were not available for analysis. Analyses of variance
with subsequent post hoc comparisons showed that both onset latency and
peak amplitude are significantly different in the RCS rats with sham
surgery compared to rats with transplants (P <
0.001).
