August 2006
Volume 47, Issue 8
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Retinal Cell Biology  |   August 2006
Visual Response Properties of Retinal Ganglion Cells in the Royal College of Surgeons Dystrophic Rat
Author Affiliations
  • Mingliang Pu
    From the School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China; the
  • Liang Xu
    Beijing Institute of Ophthalmology, Beijing TongRen Eye Center, Capital University of Medical Science, Beijing, China; and
  • Hong Zhang
    Z-BioMed, Inc., Rockville, Maryland.
Investigative Ophthalmology & Visual Science August 2006, Vol.47, 3579-3585. doi:10.1167/iovs.05-1450
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      Mingliang Pu, Liang Xu, Hong Zhang; Visual Response Properties of Retinal Ganglion Cells in the Royal College of Surgeons Dystrophic Rat. Invest. Ophthalmol. Vis. Sci. 2006;47(8):3579-3585. doi: 10.1167/iovs.05-1450.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

purpose. Alterations in retinal ganglion cell response patterns were profiled in dystrophic Royal College of Surgeons (hereafter RCS) rats over the first 100 postnatal days as a baseline for retinal rescue and vision restoration strategies. This method enabled the evaluation of the extent to which postreceptoral neuronal attributes in degenerating retinas mirror inferred declines in photoreceptor function.

methods. Single-unit responses from large retinal ganglion cells were recorded from age-matched dystrophic RCS (RCS-rdy ) and congenic RCS-p + (hereafter wild-type or wt) rats were recorded in vitro under visual control. Cells were profiled with conventional spatial and flux stimulus modulations.

results. Ganglion cell single unit and population attributes alter slowly over the course of photoreceptor degeneration in dystrophic RCS rats, with significant decreases in apparent receptive field size, contrast sensitivity, and threshold sensitivity detected by the first month of life. Spatial frequency tuning and contrast responses were extremely weak by postnatal day (P)76, paralleled by a progressive decline in signal-to-noise (S-N) ratio to roughly unity by postnatal day (P)107. This decline was only a simple loss of responsivity, as background firing rates increased substantially over time. Whereas wt retinas were dominated by ON-center cells (15/23 cells), dystrophic animals were dominated by OFF-center cells by P47 (24/27 cells).

conclusions. The first definitive signs of degeneration in dystrophic RCS rats are parallel decreases in ganglion cell threshold sensitivity and receptive field size, followed by deterioration in spatial summation. Arguably, these changes can be qualitatively explained as photoreceptor signaling losses. However, the apparent shift in population profile from ON- to OFF-center ganglion cells long before loss of the b-wave at P90 implies that a reactive mechanism such as bipolar cell rewiring and/or transformation of neuronal phenotypes occur during the early phase of photoreceptor stress, before rod and cone death.

Royal College of Surgeons (RCS) dystrophic rats exhibit progressive photoreceptor loss triggered by a phagocytosis defect in retinal pigmented epithelium cells that leads to the accumulation of cytotoxic debris in the subretinal space. 1 Photoreceptor degeneration begins at approximately postnatal day (P)20 and, by P60, there are only a few layers of photoreceptor nuclei remaining in the outer nuclear layer (ONL). 2 3 Rod degeneration is nearly complete by P100, 4 though a layer of probable cones may survive longer. The electroretinogram (ERG) a-wave is lost by P55 and the residual b-wave vanishes by P80 to P100. 5 6 The ERG is an insensitive measure of remnant cone function, as behavioral evaluations show persistent, albeit reduced, visual capacity after P100, suggesting that some remnant cones still function. Grating sensitivities of dystrophic RCS rats deteriorate from 80% of normal at P30 and finally reach total blindness by >P300 days. Acuity initially declines to 0.32 cyc/deg over the first 120 days, followed by a much slower decline thereafter. 7 The initial goal of cell-based rescue strategies is simply to prolong this period of function and, as they are much more sensitive than the ERG, physiological recordings from superior colliculus 8 and primary visual cortex 9 have been used to gauge visual functions after rescue treatments. But, given the increasing evidence of early rewiring in retinal degenerations 10 11 (for review, see Refs. 12 13 14 ), such upstream data offer only indirect and limited views of changes (if any) in retinal circuitry during degeneration. Noell 15 was the first to show that a single ganglion cell could be recorded from within the optic tract of RCS rats. Cicerone et al. 16 recorded from ganglion cell axons of RCS dystrophic rats and showed an elevated visual threshold in P90 and P150 RCS rats. Yamamoto et al. 17 found that ganglion cells in P90 to P300 RCS dystrophic rats do not respond to light. None of those studies carefully examined ganglion cell luminance sensitivity or used traditional neuronal profiling measures before P90. Although Eisenfeld et al. 18 concluded that the synaptology of the inner plexiform layer was not altered before P100 and that no impairment in retrograde transport was detectable, there is newer evidence that subtle and functionally significant alterations begin earlier. 19 20 21 Thus, a re-evaluation is essential, because the timing of intervention is critical in rescue treatments. 22 Transient rescue of retinal photoreceptor morphology and function with subretinal cell transplants has been documented by evidence from electroretinograms (ERG), 5 23 recordings from the superior colliculus 7 24 and primary visual cortex, 8 and behavioral tests. 6 25 Although these evaluations are effective in demonstrating global and indirect retinal visual function, they offer no information about single-cell activities in the actual implantation site where degeneration, circuitry reorganization, and rescue concurrently occur. The goal of the present study was to profile quantitatively the individual ganglion cell visual response properties in P30 to P100 RCS rats as baseline information for retinal rescue and treatment. 
Materials and Methods
Animals
Forty-two pigmented RCS rats of either sex (27 dystrophic: RCS-rdy ) and 15 nondystrophic (RCS-p +) were used in the experiments (Table 1) . Ranging in age from P28 to P119, they were housed in a 12-hour light-dark cycle and provided food and water ad libitum. All experiments were performed in accordance with institutional guidelines and the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. 
In Vitro Preparation
The retinal preparation has been described previously and is based on the in vitro methods developed in the Berson laboratory for recording feline retinal ganglion cells. 26 27 Under dim red light, the lens was removed, and the vitreous was carefully removed with fine tip forceps. The eyecup was mounted flat, sclera side down, directly on the bottom of a recording chamber. Because the rat retina easily detaches from the pigment epithelium, it was held in place by a nylon mesh retaining ring and was superfused by Ames medium (Sigma-Aldrich, St. Louis, MO) at a fixed rate (3 mL/min) at room temperature. 
Computer Generated Visual Stimulation
Visual stimulation paradigms have been described previously. 26 27 Briefly, visual stimuli were generated by programming a graphics card (Matrox Millennium 3000), displayed on a 5-in. B/W SVGA CRT monitor (Kristel Corp., St. Charles, IL) and imaged with a first-surface mirror and lens (Edmond Scientific, Barrington, NJ) on the film plane of the microscope’s camera port. This method ensured that, when the electrode tip was in focus in the eyepieces, the stimulus was also sharply focused. CRT stimulus luminance ranged over 46 to 183 cd/m2. The background luminance levels on CRT in the absence of stimulation were close to 0.4 cd/m2. During this experiment, a Zeiss 40× water-immersion objective lens was used (Carl Zeiss Meditec, Inc., Thornwood, NY). With this objective, the intensity was reduced from 46 to 183 cd/m2 on a CRT to 0.08 to 0.69 cd/m2 on the retina. The intensity was further attenuated by using different combinations of neutral density filters (Oriel Corp., Stratford, CT). The intensity of visual stimulation was measured with a digital photometer (IL 1400A; International Light, Inc., Newburyport, MA). 
Data Collection and Analysis
Visual responses were recorded by a glass microelectrode (R = 2–5 MΩ), amplified by the intracellular amplifier (IR283; Neurodata Inc., Delaware Water, PA), and digitized (Digidata 1200 system; Axon Instrument, Inc., Forest City, CA). The amplified signal was sent to an audio monitor to estimate visual threshold. After visualization with 0.002% acridine orange (Sigma-Aldrich), ganglion cells were selected for recording. Since rat retina ganglion cells are heterogeneous, to simplify the analysis and effectively evaluate the impacts of dystrophic degeneration on retinal ganglion cells, we selectively recorded from a group of large-soma ganglion cells (20–25-μm diameter somas). Based on published data, the range of soma diameter fell into the α-cell category in rat. 28 A receptive field (RF) was determined by two methods: (1) mapping the RF with a 0.2° light spot on at a low mesopic intensity background (≈0.01 cd/m2). The spot was turned on and off while it was moved to various regions within the RF. Once the polarity of the RF was established, the spot was moved to a peripheral region of the field to determine the edge of RF; and (2) running an area–threshold visual stimulation program to determine the best stimulus size that evoked the maximum discharge. The spot size that evoked maximum responses in the area threshold test was selected for the luminance sensitivity and signal-to-noise (S-N) ratio analysis. The RF center size was quantitatively determined by using smoothed Gaussian fit to the number of spikes collected from the area–threshold test. For studies of responses to sinusoidal contrast gratings, we applied conventional Fourier analysis techniques 29 to post stimulus–time histograms to determine the amplitudes of response components at the frequency of stimulation and at the second harmonic. The histograms were based on unit responses to at least eight stimulus cycles. Incremental threshold luminance sensitivities and other response property tests followed previously published methods. 26 27 In general, a criterion response was obtained by adjusting the stimulus luminance, and the evoked impulse trains to 10 presentations (two cycles each) of the stimulus were summed to yield each histogram. A firing rate of two spikes per second above the baseline rate was set as a threshold response. If none of the test stimuli produced exactly two spikes per second, threshold was determined by linear interpolation. This difference also matched our subjective auditory criteria. The acquired data were further analyzed off-line (pCLAMP9 software; Axon Corp., San Mateo, CA). Additional data analysis including fast Fourier analysis was performed on computer (Microsoft Excel; Microsoft Corp., Redmond, WA). 
Results
We recorded from 73 ganglion cells from dystrophic RCS rats at intervals of P28–30, P36–37, P47–48, P60–67, P76, and P107–108) and 46 cells from wt rats. The key goal was to characterize the loss of ganglion cell responsivity, especially in view of recent evidence suggesting that reorganization of retinal circuits in retinal degeneration may precede photoreceptor death (for reviews see Refs. 12 13 14 ). Figures 1A and 1Cillustrate the responses to a test spot positioned over the RF center of a ganglion cell from a wt rat. As the spot turned off, it evoked crisp OFF discharges (Figs. 1A 1C) . A cell we identified as having similar RF properties in a P107 dystrophic rat (Figs. 1B 1D)did not show the same well-defined response patterns. The dystrophic cell exhibited numerous spontaneous spikes but responded only (and weakly) to the first stimulus trial. The S-N ratio of the wt cell is more than 20 times higher than the dystrophic one (Fig. 1E) . Indeed, most cells from P107 to P108 responded only in the first one or two trials and failed thereafter. Because the loss of rod or cone photon capture due to a decline in visual pigment content does not predict such a fatigue effect, we concluded that a careful screening of ganglion cell response properties might expose characteristic changes in retinal circuitry or signal processing in retinal degenerations. We investigated the dystrophic impact on RF size, ON- and OFF-cell encounter frequency, luminance sensitivity, frequency tuning, contrast response, and S-N ratio over the intervals described earlier, spanning a 100-fold decline in luminance sensitivity in the dystrophic animals. 
S-N Ratio
Ganglion cells collect signals from noisy synaptic inputs that are integrated into graded potentials and then converted to a spike train. 30 When a ganglion cell loses its primary drive through the photoreceptor[b]→bipolar cell circuitry, one of the effects is a change in the S-N ratio (S-N = average driven firing/second versus spontaneous firing/second). Indeed, as shown in Figure 2 , we observed a progressive decline in S-N and with a reduction of 49% already by P28–30 in the dystrophic animals. Luminance, spatial, and contrast sensitivities of these animals seemed unimpaired, and this implies a decreased discrimination of system signal and noise, though we cannot determine its source. The S-N ratio continued to decline until it reached an average of 0.93 for cells from P107–108 animals. This reflects a near total loss in the ability of ganglion cells to encode visual signals reliably and, as the data in Figure 1imply, is the result of both an increase in spontaneous firing and a decrease in the robustness of light-driven signaling. 
RF Size
Pavlidis et al. 19 recently used retrograde transport of the fluorescent dye 4Di-10ASP to reveal a large decrease in labeled ganglion cell dendrites in RCS rats at P30 to P90. None were labeled in RCS rats at P180. As there is a strong correlation between physiologically defined RF and dendritic field size, 31 and ganglion cell spatial integration may decline by processes more complex than the simple loss of rod and cone signals. We estimated ganglion cell RF size to be similar using both the flashing spot and increment area threshold methods. Figure 3shows that, compared with wt animals, there was no major difference in aggregate dystrophic ganglion cell RF size at P28 to P30 but a significant reduction to 80% was detected by P36 to P37 (P < 0.002, t-test). Although there was a continued downward trend, the incremental change was not significant. Clearly, combining data from several kinds of ganglion cells (even when restricted to the large cell group) will underestimate changes in specific cells, and the general increase in coefficient of variation suggests that RF shrinkage is uneven across ganglion cells. 
RF Polarity
Although visual response properties of ganglion cells in the RCS rat have been documented previously 16 17 the impact of degeneration on ON- and OFF-channels has not been systematically investigated. To simplify analysis, we only recorded from large cells that resemble RGA2 cells, 28 and RF polarity was determined by turning a 1° spot on and off in various locations within the field (Fig. 4) . During the first month after birth, a similar number of ON and OFF cells were encountered in dystrophic rats, whereas most were ON cells in wt animals. Previous in vivo recordings from the optic nerves of Long-Evans hooded rats show somewhat different results (25 OFF and 29 ON cells), 32 suggesting that we might actually have had a slight bias for ON cells in visually guided recording. However, more OFF cells were recorded (P < 0.001, t-test) by P47 to P48, and the pattern persisted with age, in contrast to rats of any age and strain previously reported. These data imply that the ON pathway is somehow preferentially disconnected from ganglion cells early in the degeneration process. 
Luminance Sensitivity
The deconstruction and death of photoreceptors in the RCS rat is accompanied by gradual changes in the ERG, 1 4 including clear deficits in ON bipolar cell signaling by P30. 19 Because rod and cone death are not significantly distinct and presuming that OFF bipolar cells are also affected, we anticipated a progressive depression of ganglion cell luminance sensitivity (Fig. 5) . Indeed, a 0.5-log-unit decline in luminance sensitivity can be detected in P28–30 dystrophic rats. 
As shown in Figure 5 , the sensitivity slowly decreased and appeared to enter a second phase at P60, with a further ≈1-log-unit loss in sensitivity. The depressed sensitivity of P107–108 animals is in agreement with previous physiological observations. 15 23 Furthermore, the luminance sensitivity of ON cells is substantially and preferentially depressed in older animals and the variation is very large. The mean (OFF-ON) sensitivity difference was 0.25 log units in P28–30 animals and increased to 0.71 by P47 to P48. In contrast, ON cells become progressively rare, and these phenomena are probably related. Indeed, one of the surviving ON cells was a “luminance detector.” The discharge rate of this cell class (rarely encountered in any species) is directly proportional to luminance. Of 119 cells recorded, only two luminance detectors were identified. Considering the low encounter rates of such cells, it is possible (but only an impression) that luminance detectors are resistant to degeneration, as might be predicted if they were melanopsin-containing cells. 33  
Spatial Frequency Tuning
Dystrophic RCS rats demonstrate depressed spatial frequency responses in a free-viewing paradigm 7 consistent with loss of photoreceptors. Similarly, the spatial frequency responses of ganglion cells to drifting gratings in dystrophic rats deteriorate with age (Fig. 6) . However, the response profile at P28 to P30 was little different from that of wt rats. By P47 to P48 and P60 to P67 the response amplitude declined more than one third in the 0.07 to 0.09-cyc/deg range. By P76, the discharges could not be modulated by sinusoidal gratings of any frequencies, consistent with the massive loss in overall luminance sensitivity. 
Contrast Response
Ganglion cell responses to the contrast of sinusoidal gratings gauges both center sensitivity and surround efficacy in tuning spatial responses. Cells from wt and P28–30 dystrophic rats showed a monotonic linear increase in response histogram amplitude with contrast, whereas cells from P47–48 and P60–67 retinas, in contrast, showed a sharp decline in response to 100% contrast gratings of 0.07 cyc/deg (Fig. 7) . After P76, dystrophic animals did not respond significantly to grating stimulations of any contrast or spatial frequency. Although all these measures are roughly consistent with loss of photoreceptor function, it is not immediately clear why reduced photon capture (for example) should lead to loss of drifting grating-driven responses in cells that average over many receptors and whose contrast tuning depend on surround mechanisms. Furthermore, it is unclear why contrast or spatial frequency tuning abruptly decreased in just 9 days (from P67 to P76). Understanding mechanisms underlying this drastic change should be the goal of future investigations. 
Discussion
The present study reveals that the ganglion cell single unit and population attributes alter slowly over the course of photoreceptor degeneration in dystrophic RCS rats, with significant decreases in apparent RF size, contrast sensitivity, and threshold sensitivity detected by the first month of life. Spatial frequency tuning and contrast responses were extremely weak by P76, paralleled by a progressive decline in S-N ratio to roughly unity by P107. This decline was not only a simple loss of responsivity but also a decrease in the signal, as background firing rates increased substantially over time. Whereas wt retinas were dominated by ON-center cells, dystrophic animals were dominated by OFF-center cells by P47. Taken together, our data suggest two phases of functional degeneration in the dystrophic RCS rat retina. During the first 2 months after birth, during the phase of photoreceptor stress in the RCS model, the aggregate ganglion cell cohort shows a gradual decline in luminance sensitivity and S-N ratio. After that, all sensitivity measures (except RF size) show further declines, consistent with extensive phase-2 photoreceptor death. 
S-N Ratio
In the present study, the S-N ratio decreased in fast and slow phases, though additional complexities emerged. As shown in Figure 1B , a cell’s basic ability to discharge amplitude appeared to be normal, but they responded only weakly to the first visual stimulation. This cell, like all cells in this age group, had a very low S-N ratio (0.91). We also encountered cells that did not respond to any visual stimulation, and spontaneous spike rates were lower. This complex loss in signal fidelity is not easily explained by simple losses of photon capture and losses in basic photoreceptor to bipolar cell glutamatergic drive. Indeed it suggests, but does not prove, that intrinsic network signaling becomes unmasked by loss of sensory drive. Similarly, spontaneous-activity, high-frequency rhythmic firing among retinal ganglion cells increases dramatically in the rd1 mouse model as outer retinal degeneration occurs and rod signals disappear (Stasheff RF, et al. IOVS 2004;45:ARVO E-Abstract 5070). 
RF Size
In the present study, the change in RF size occurred quite early (P36–37) and then leveled off. This does not match the time course of the decrease in 4Di-10ASP-filled dendritic fields from P30 to P90. 18 This mismatch could be interpreted as follows: first, recent immunocytochemical staining shows that synaptic connection between photoreceptors and their target cells is already impaired at P21. 34 Second, the time course of decrease in 4Di-10ASP-filled dendritic fields offers a general response profile of all superior colliculus (SC) projecting ganglion cells. Thus, it cannot accurately reveal changes in a subpopulation of SC-projecting ganglion cells. Specifically, the range of soma sizes in the cells we recorded fell into the category of α-cells in the rat, 28 which comprises only 2% to 4% of all ganglion cells in this species. 35 As we held background luminance constant and selected only for large ganglion cells corresponding to the RGA2 subgroup, 28 36 the relatively rapid initial decline in RF probably represents alterations in the ability of ganglion cells to integrate signals from other retinal neurons, rather than simple loss in photoreceptor efficacy. Thus, as decrease in luminance sensitivity observed in this experiment, the decreased RF size can be explained by the fact that a larger portion of the “tail” of the RF profile decline below the threshold for the measurement by our methods. 
At later stages (>P180), there is progressive loss of ganglion cells measured by retrograde transport partly due to the variable constriction of trapped axons by ingrowing vessels. 37 Even more extensive alterations such as cell death, migration, and rewiring 12 14 clearly further corrupt ganglion cell function. Indeed, there is also evidence of the emergence of new ganglion cell axons that course through the retina and may even invade the choroid. 30 33 Additional evidence of neural remodeling separate from photoreceptor death is the loss of 4Di-10ASP transport into ganglion cell dendrites of the dystrophic RCS rat between P30 and P90, culminating in the inability to label dendrites in the RCS rat by P180. 18 Whether this is a failure of transport or actual loss of dendrites cannot be determined, but it does argue that ganglion cells are functionally stressed long before photoreceptors die. 
RF Polarity
Although there is no direct evidence that reveals any ganglion cell subclass to be more vulnerable than another, the increase in covariance of luminance sensitivities and the switch in the frequencies at which ON to OFF cells were encountered implies a heterogeneous response to the loss of photoreceptor signaling. Encountering more OFF than ON ganglion cells during degeneration was unexpected. We do not believe that any sampling bias produced this effect, given that more ON cells were encountered in congenic wt rats when we used the same techniques. Indeed, we recorded more OFF cells in dystrophic rats in every age group. This finding is in agreement with a previous report 20 that revealed bipolar cells were still active around P33 in the RCS rat, but that the synaptic function of on-bipolar cells, especially rod bipolar cells was impaired. Consequently, it is possible that there are different inhibitory mechanisms for ON and OFF ganglion cells. Indeed, the OFF ganglion cell is inhibited by the ON pathway but not vice versa (i.e., the inhibition is unidirectional). 38 Because the ON pathway is severely damaged in the RCS rat, the effectiveness of ON pathway inhibition of OFF ganglion cells could be diminished. The ON pathway, therefore, appears to be more vulnerable to dystrophic events. Another interpretation of the apparent ON→OFF encounter bias might be that the process of switching dendrites from rods to cones as manifested by rod bipolar cells in other degeneration models eventually corrupts ON pathways. 10 39 The fact that the b-wave does not recover at all from this switch implies that any new cone[b]→rod bipolar cell synapses are not effective or perhaps not even mGluR6 mediated. For instance, immunostaining shows that mGluR6 is already impaired at P21 40 implying postsynaptic ON-bipolar cells have already lost their connections with photoreceptors at early stage after birth. 
Luminance Sensitivity
Our results show that the luminance sensitivity of RCS ganglion cells decreases 0.54 log unit by P30, 1 log unit by P60 to P67, and 1.88 log units by P76. It is presently unclear why loss of sensitivity is biphasic, but the evidence suggests that temporally separated periods of photoreceptor stress and death have separable epochs of visual loss. This possibility could have implications for profiling visual functions in human photoreceptor degenerations if the earliest hallmark of disease is a loss of neural responsiveness downstream from the rods and cones themselves. 
Spatial Frequency Tuning
In agreement with previous observations, 16 spatial frequency tuning in dystrophic RCS rats was normal during the first month but then deteriorated with age. In line with results from behavioral studies, 7 we observed a sudden decrease in spatial frequency response during the second month. In contrast to these behavioral studies, cells recorded from P76–108 animals did not respond to any spatial frequencies. Of course, the large cells from which we recorded are probably not the cellular substrate for high acuity. Using free viewing, 7 acuity is a complex mixture of retinal cell survival and head scanning, and only a small number of small ganglion cells may suffice to support detection. 
Contrast Response
Compared with wt and P28–30 dystrophic rats, cells from P47–48 and P60–67 retinas showed a sharp decline in response to 100% contrast gratings (Fig 6) . This result implies that retinal neurocircuitry undergoes substantial reorganization that in turn affects ganglion cell surround mechanisms. The loss of photoreceptors could be a trigger for such an event. Once this event is activated, it could quickly affect ganglion cell surround mechanisms. Indeed, we observed a fast paced deterioration to contrast responses in P46–47 animals but little response left in P76 retinas. 
In recent years, many attempts have been made in different degeneration models to rescue photoreceptors including transplants of retinal sheets, 22 41 human and nonhuman pigment epithelium cells, 6 16 42 Schwann cell lines, 25 brain-derived precursor cells, 40 putative stem cells, 43 and gene transfer. 44 45 The ultimate goal of these efforts is restore vision. The beneficial effect of these procedures probably involves two mechanisms: the rescue of host photoreceptors via trophic mechanisms and possible re-establishment of synaptic connectivity between transplant and host retina, though the latter seems problematic. 13 As recent evidence shows that degenerative retina actively remodels, 12 13 14 the functionality of retinal neurocircuitry deserves more detailed assessment. Our data suggest that simultaneous photoreceptor loss and losses in signaling efficacy are mixed during retinal degeneration and it is not clear whether the latter are reversible. This may seriously constrain rescue opportunities in human disease. 
 
Table 1.
 
Luminance Threshold
Table 1.
 
Luminance Threshold
Age (PN Days) ON-Center OFF-Center
Cells (n) Mean Lum. (cd/m2) SD Cells (n) Mean Lum. (cd/m2) SD
28–30 7 −2.23 0.41 8 −2.48 0.55
36–37 3 −2.08 0.97 5 −2.10 0.55
47–48 1 −1.40 0.00 7 −2.11 0.46
Figure 1.
 
Response patterns of RCS rat retinal ganglion cells to visual stimulation. (A) A representative OFF-center retinal ganglion cell recorded from 31-day-old wt RCS rat. This cell responded to a dark spot centered on the RF, presented for the interval indicated by the stimulus marker at the bottom. The offset of a spot is indicated by the upward deflection of the square wave, and the onset of the spot is represented by the baseline. Note this cell’s visual discharges were modulated by the testing spot: Spot diameter, 1.5°; onset duration, 0.5 second; background, 0.1 cd/m2. (B) A typical ganglion cell from a 107-day-old dystrophic RCS rat responded to onset of a dark spot centered on the RF. This cell showed distinguishable responses only to the first dark spot. (C) Histogram of the wt ganglion cell discharge pattern, bin width 500 ms. (D) Histogram of the dystrophic ganglion cell discharge pattern, bin width 500 ms. This cell was not responsive to the test spot afterward but showed vigorous spontaneous discharges: spot diameter, 3.2°; onset duration, 0.5 second; background, 0.1 cd/m2. (E) The insert illustrates the number of spikes counted for visual and spontaneous activities during the 5 seconds of sampling period shown. The number of spontaneous discharges increased more than 20-fold in P107 dystrophic rat. The scale denotes discharge amplitudes and time scale.
Figure 1.
 
Response patterns of RCS rat retinal ganglion cells to visual stimulation. (A) A representative OFF-center retinal ganglion cell recorded from 31-day-old wt RCS rat. This cell responded to a dark spot centered on the RF, presented for the interval indicated by the stimulus marker at the bottom. The offset of a spot is indicated by the upward deflection of the square wave, and the onset of the spot is represented by the baseline. Note this cell’s visual discharges were modulated by the testing spot: Spot diameter, 1.5°; onset duration, 0.5 second; background, 0.1 cd/m2. (B) A typical ganglion cell from a 107-day-old dystrophic RCS rat responded to onset of a dark spot centered on the RF. This cell showed distinguishable responses only to the first dark spot. (C) Histogram of the wt ganglion cell discharge pattern, bin width 500 ms. (D) Histogram of the dystrophic ganglion cell discharge pattern, bin width 500 ms. This cell was not responsive to the test spot afterward but showed vigorous spontaneous discharges: spot diameter, 3.2°; onset duration, 0.5 second; background, 0.1 cd/m2. (E) The insert illustrates the number of spikes counted for visual and spontaneous activities during the 5 seconds of sampling period shown. The number of spontaneous discharges increased more than 20-fold in P107 dystrophic rat. The scale denotes discharge amplitudes and time scale.
Figure 2.
 
S-N ratio in ganglion cells of different age groups. The spot diameter that evoked maximum responses in area threshold test was selected for the S-N ratio test. The visual stimulation presentation consisted of four trials. Each trial had eight cycles and each cycle ran for 8 seconds. After each presentation, visual evoked discharges were averaged as signal and spontaneous responses 1 second before and after each cycle were collected as noise. Note there was a 50% decrease in average S-N ratio during the first month after birth. The S-N ratio continued to decline until it reached an average value of 0.93 for cells from P108–109 animals. Wt (10.14 ± 3.43, n = 20); P28–30 (4.96 ± 1.95, n = 14,); P36–37 (2.93 ± 1.45, n = 14); P47–48 (2.53 ± 0.78, n = 9); P61–67 (1.77 ± 0.76, n = 5); P76 (1.45 ± 0.3, n = 4); P107–108 (0.93 ± 0.24, n = 12).
Figure 2.
 
S-N ratio in ganglion cells of different age groups. The spot diameter that evoked maximum responses in area threshold test was selected for the S-N ratio test. The visual stimulation presentation consisted of four trials. Each trial had eight cycles and each cycle ran for 8 seconds. After each presentation, visual evoked discharges were averaged as signal and spontaneous responses 1 second before and after each cycle were collected as noise. Note there was a 50% decrease in average S-N ratio during the first month after birth. The S-N ratio continued to decline until it reached an average value of 0.93 for cells from P108–109 animals. Wt (10.14 ± 3.43, n = 20); P28–30 (4.96 ± 1.95, n = 14,); P36–37 (2.93 ± 1.45, n = 14); P47–48 (2.53 ± 0.78, n = 9); P61–67 (1.77 ± 0.76, n = 5); P76 (1.45 ± 0.3, n = 4); P107–108 (0.93 ± 0.24, n = 12).
Figure 3.
 
Diameters of the RF centers of dystrophic RCS rat ganglion cells in different age groups. The RF centers were measured in vitro. The RF center size was quantitatively determined by using smoothed Gaussian fit to number of spikes collected from the area–threshold test. The column at the extreme left represents the average RF center diameter in wt animals and the remaining columns are average RF center sizes in different age groups of dystrophic animals. There was a sudden decrease in RF center sizes during the first week of the second month (P36–37), Vertical bars, SE. Congenic wt (n = 20, SEM = 55); P28–30 (n = 13, SEM = 58); P36–37 (n = 15, SEM = 49), P47–48 (n = 7, SEM = 57); P60–67 (n = 5, SEM = 69). P76 (n = 6, SEM = 61), P107–108 (n = 9, SEM = 42).
Figure 3.
 
Diameters of the RF centers of dystrophic RCS rat ganglion cells in different age groups. The RF centers were measured in vitro. The RF center size was quantitatively determined by using smoothed Gaussian fit to number of spikes collected from the area–threshold test. The column at the extreme left represents the average RF center diameter in wt animals and the remaining columns are average RF center sizes in different age groups of dystrophic animals. There was a sudden decrease in RF center sizes during the first week of the second month (P36–37), Vertical bars, SE. Congenic wt (n = 20, SEM = 55); P28–30 (n = 13, SEM = 58); P36–37 (n = 15, SEM = 49), P47–48 (n = 7, SEM = 57); P60–67 (n = 5, SEM = 69). P76 (n = 6, SEM = 61), P107–108 (n = 9, SEM = 42).
Figure 4.
 
Histogram comparing the number of ON and OFF ganglion cells recorded from dystrophic RCS rats as a function of age. The polarities of RF centers were determined by using a test spot. The extreme left columns represent number of ON and OFF ganglion cells encountered in wt animals. The remaining columns are the ganglion cells recorded from dystrophic RCS rats of different age groups. The chance of encountering ON center ganglion cells drastically declined after P36–37, whereas OFF cells were still recorded, even in the P107–108 age group.
Figure 4.
 
Histogram comparing the number of ON and OFF ganglion cells recorded from dystrophic RCS rats as a function of age. The polarities of RF centers were determined by using a test spot. The extreme left columns represent number of ON and OFF ganglion cells encountered in wt animals. The remaining columns are the ganglion cells recorded from dystrophic RCS rats of different age groups. The chance of encountering ON center ganglion cells drastically declined after P36–37, whereas OFF cells were still recorded, even in the P107–108 age group.
Figure 5.
 
Progressive threshold luminance elevation in dystrophic RCS rats. Each data point represents an averaged threshold luminance for each age group. The test spot was adjusted to match the center size of the RF. Ganglion cells were dark adapted for 40 minutes before entering the sensitivity test. The luminance intensity at the retinal surface without neutral density filters ranged from 0.08 to 0.69 cd/m2 and background was 0.01 cd/m 2 . The intensity was attenuated with a set of neutral-density filters with 0.1 to 4 log units of attenuation. For each intensity, four trials were performed. Each trial consisted of eight circles, and each circle lasted for 2 seconds. Error bars, SE. The threshold luminance of wt RCS rats is used as control. Number of cells in each age group: congenic wt (n = 7, SEM = 0.75); P28–30 (n = 15, SEM = 0.21); P36–37 (n = 8, SEM = 0.49), P47–48 (n = 8, SEM = 57); P60–67 (n = 5, SEM = 69). P76 (n = 4, SEM = 61), P107–108 (n = 7, SEM = 42).
Figure 5.
 
Progressive threshold luminance elevation in dystrophic RCS rats. Each data point represents an averaged threshold luminance for each age group. The test spot was adjusted to match the center size of the RF. Ganglion cells were dark adapted for 40 minutes before entering the sensitivity test. The luminance intensity at the retinal surface without neutral density filters ranged from 0.08 to 0.69 cd/m2 and background was 0.01 cd/m 2 . The intensity was attenuated with a set of neutral-density filters with 0.1 to 4 log units of attenuation. For each intensity, four trials were performed. Each trial consisted of eight circles, and each circle lasted for 2 seconds. Error bars, SE. The threshold luminance of wt RCS rats is used as control. Number of cells in each age group: congenic wt (n = 7, SEM = 0.75); P28–30 (n = 15, SEM = 0.21); P36–37 (n = 8, SEM = 0.49), P47–48 (n = 8, SEM = 57); P60–67 (n = 5, SEM = 69). P76 (n = 4, SEM = 61), P107–108 (n = 7, SEM = 42).
Figure 6.
 
Spatial frequency tuning curves for ganglion cells recorded from congenic wt and dystrophic RCS rats. Ganglion cells responded to a sinusoidal contrast grating drifted across the RF. Spatial frequency of the grating was within a degree of visual angle (cyc/deg). The temporal frequency of the grating was held constant at 1 Hz; contrast was 100%; average luminance on retinal surface 0.3 cd/m2. Response amplitudes shown represent the normalized average magnitude of the first harmonic component of the Fourier decomposition. Note the sudden decreases in response amplitudes at low spatial frequencies in P47–48 and P60–67 animals. Ganglion cells recorded from P76 animals did not respond to any spatial frequency of the grating. Symbols denote different age groups: ○, congenic wt; □, 28–30; Δ, 47–48; ×, 60–67; *, 76.
Figure 6.
 
Spatial frequency tuning curves for ganglion cells recorded from congenic wt and dystrophic RCS rats. Ganglion cells responded to a sinusoidal contrast grating drifted across the RF. Spatial frequency of the grating was within a degree of visual angle (cyc/deg). The temporal frequency of the grating was held constant at 1 Hz; contrast was 100%; average luminance on retinal surface 0.3 cd/m2. Response amplitudes shown represent the normalized average magnitude of the first harmonic component of the Fourier decomposition. Note the sudden decreases in response amplitudes at low spatial frequencies in P47–48 and P60–67 animals. Ganglion cells recorded from P76 animals did not respond to any spatial frequency of the grating. Symbols denote different age groups: ○, congenic wt; □, 28–30; Δ, 47–48; ×, 60–67; *, 76.
Figure 7.
 
Effect of grating contrast on response magnitude of ganglion cells recorded in vitro. Ganglion cells responded to a grating of 0.07 cyc/deg drifted at a fixed temporal frequency (1 Hz). Response amplitude represents the normalized average magnitude of the first harmonic component of the Fourier decomposition. Note the reduced response amplitudes at 100% contrast in P47–49 and P60-P67 animals and little contrast response left in P76 animals. Symbols depict the same age groups as in Figure 6 .
Figure 7.
 
Effect of grating contrast on response magnitude of ganglion cells recorded in vitro. Ganglion cells responded to a grating of 0.07 cyc/deg drifted at a fixed temporal frequency (1 Hz). Response amplitude represents the normalized average magnitude of the first harmonic component of the Fourier decomposition. Note the reduced response amplitudes at 100% contrast in P47–49 and P60-P67 animals and little contrast response left in P76 animals. Symbols depict the same age groups as in Figure 6 .
The authors thank Robert Marc for critical input and comments and Steven Fisher for proofreading and editing the manuscript. 
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Figure 1.
 
Response patterns of RCS rat retinal ganglion cells to visual stimulation. (A) A representative OFF-center retinal ganglion cell recorded from 31-day-old wt RCS rat. This cell responded to a dark spot centered on the RF, presented for the interval indicated by the stimulus marker at the bottom. The offset of a spot is indicated by the upward deflection of the square wave, and the onset of the spot is represented by the baseline. Note this cell’s visual discharges were modulated by the testing spot: Spot diameter, 1.5°; onset duration, 0.5 second; background, 0.1 cd/m2. (B) A typical ganglion cell from a 107-day-old dystrophic RCS rat responded to onset of a dark spot centered on the RF. This cell showed distinguishable responses only to the first dark spot. (C) Histogram of the wt ganglion cell discharge pattern, bin width 500 ms. (D) Histogram of the dystrophic ganglion cell discharge pattern, bin width 500 ms. This cell was not responsive to the test spot afterward but showed vigorous spontaneous discharges: spot diameter, 3.2°; onset duration, 0.5 second; background, 0.1 cd/m2. (E) The insert illustrates the number of spikes counted for visual and spontaneous activities during the 5 seconds of sampling period shown. The number of spontaneous discharges increased more than 20-fold in P107 dystrophic rat. The scale denotes discharge amplitudes and time scale.
Figure 1.
 
Response patterns of RCS rat retinal ganglion cells to visual stimulation. (A) A representative OFF-center retinal ganglion cell recorded from 31-day-old wt RCS rat. This cell responded to a dark spot centered on the RF, presented for the interval indicated by the stimulus marker at the bottom. The offset of a spot is indicated by the upward deflection of the square wave, and the onset of the spot is represented by the baseline. Note this cell’s visual discharges were modulated by the testing spot: Spot diameter, 1.5°; onset duration, 0.5 second; background, 0.1 cd/m2. (B) A typical ganglion cell from a 107-day-old dystrophic RCS rat responded to onset of a dark spot centered on the RF. This cell showed distinguishable responses only to the first dark spot. (C) Histogram of the wt ganglion cell discharge pattern, bin width 500 ms. (D) Histogram of the dystrophic ganglion cell discharge pattern, bin width 500 ms. This cell was not responsive to the test spot afterward but showed vigorous spontaneous discharges: spot diameter, 3.2°; onset duration, 0.5 second; background, 0.1 cd/m2. (E) The insert illustrates the number of spikes counted for visual and spontaneous activities during the 5 seconds of sampling period shown. The number of spontaneous discharges increased more than 20-fold in P107 dystrophic rat. The scale denotes discharge amplitudes and time scale.
Figure 2.
 
S-N ratio in ganglion cells of different age groups. The spot diameter that evoked maximum responses in area threshold test was selected for the S-N ratio test. The visual stimulation presentation consisted of four trials. Each trial had eight cycles and each cycle ran for 8 seconds. After each presentation, visual evoked discharges were averaged as signal and spontaneous responses 1 second before and after each cycle were collected as noise. Note there was a 50% decrease in average S-N ratio during the first month after birth. The S-N ratio continued to decline until it reached an average value of 0.93 for cells from P108–109 animals. Wt (10.14 ± 3.43, n = 20); P28–30 (4.96 ± 1.95, n = 14,); P36–37 (2.93 ± 1.45, n = 14); P47–48 (2.53 ± 0.78, n = 9); P61–67 (1.77 ± 0.76, n = 5); P76 (1.45 ± 0.3, n = 4); P107–108 (0.93 ± 0.24, n = 12).
Figure 2.
 
S-N ratio in ganglion cells of different age groups. The spot diameter that evoked maximum responses in area threshold test was selected for the S-N ratio test. The visual stimulation presentation consisted of four trials. Each trial had eight cycles and each cycle ran for 8 seconds. After each presentation, visual evoked discharges were averaged as signal and spontaneous responses 1 second before and after each cycle were collected as noise. Note there was a 50% decrease in average S-N ratio during the first month after birth. The S-N ratio continued to decline until it reached an average value of 0.93 for cells from P108–109 animals. Wt (10.14 ± 3.43, n = 20); P28–30 (4.96 ± 1.95, n = 14,); P36–37 (2.93 ± 1.45, n = 14); P47–48 (2.53 ± 0.78, n = 9); P61–67 (1.77 ± 0.76, n = 5); P76 (1.45 ± 0.3, n = 4); P107–108 (0.93 ± 0.24, n = 12).
Figure 3.
 
Diameters of the RF centers of dystrophic RCS rat ganglion cells in different age groups. The RF centers were measured in vitro. The RF center size was quantitatively determined by using smoothed Gaussian fit to number of spikes collected from the area–threshold test. The column at the extreme left represents the average RF center diameter in wt animals and the remaining columns are average RF center sizes in different age groups of dystrophic animals. There was a sudden decrease in RF center sizes during the first week of the second month (P36–37), Vertical bars, SE. Congenic wt (n = 20, SEM = 55); P28–30 (n = 13, SEM = 58); P36–37 (n = 15, SEM = 49), P47–48 (n = 7, SEM = 57); P60–67 (n = 5, SEM = 69). P76 (n = 6, SEM = 61), P107–108 (n = 9, SEM = 42).
Figure 3.
 
Diameters of the RF centers of dystrophic RCS rat ganglion cells in different age groups. The RF centers were measured in vitro. The RF center size was quantitatively determined by using smoothed Gaussian fit to number of spikes collected from the area–threshold test. The column at the extreme left represents the average RF center diameter in wt animals and the remaining columns are average RF center sizes in different age groups of dystrophic animals. There was a sudden decrease in RF center sizes during the first week of the second month (P36–37), Vertical bars, SE. Congenic wt (n = 20, SEM = 55); P28–30 (n = 13, SEM = 58); P36–37 (n = 15, SEM = 49), P47–48 (n = 7, SEM = 57); P60–67 (n = 5, SEM = 69). P76 (n = 6, SEM = 61), P107–108 (n = 9, SEM = 42).
Figure 4.
 
Histogram comparing the number of ON and OFF ganglion cells recorded from dystrophic RCS rats as a function of age. The polarities of RF centers were determined by using a test spot. The extreme left columns represent number of ON and OFF ganglion cells encountered in wt animals. The remaining columns are the ganglion cells recorded from dystrophic RCS rats of different age groups. The chance of encountering ON center ganglion cells drastically declined after P36–37, whereas OFF cells were still recorded, even in the P107–108 age group.
Figure 4.
 
Histogram comparing the number of ON and OFF ganglion cells recorded from dystrophic RCS rats as a function of age. The polarities of RF centers were determined by using a test spot. The extreme left columns represent number of ON and OFF ganglion cells encountered in wt animals. The remaining columns are the ganglion cells recorded from dystrophic RCS rats of different age groups. The chance of encountering ON center ganglion cells drastically declined after P36–37, whereas OFF cells were still recorded, even in the P107–108 age group.
Figure 5.
 
Progressive threshold luminance elevation in dystrophic RCS rats. Each data point represents an averaged threshold luminance for each age group. The test spot was adjusted to match the center size of the RF. Ganglion cells were dark adapted for 40 minutes before entering the sensitivity test. The luminance intensity at the retinal surface without neutral density filters ranged from 0.08 to 0.69 cd/m2 and background was 0.01 cd/m 2 . The intensity was attenuated with a set of neutral-density filters with 0.1 to 4 log units of attenuation. For each intensity, four trials were performed. Each trial consisted of eight circles, and each circle lasted for 2 seconds. Error bars, SE. The threshold luminance of wt RCS rats is used as control. Number of cells in each age group: congenic wt (n = 7, SEM = 0.75); P28–30 (n = 15, SEM = 0.21); P36–37 (n = 8, SEM = 0.49), P47–48 (n = 8, SEM = 57); P60–67 (n = 5, SEM = 69). P76 (n = 4, SEM = 61), P107–108 (n = 7, SEM = 42).
Figure 5.
 
Progressive threshold luminance elevation in dystrophic RCS rats. Each data point represents an averaged threshold luminance for each age group. The test spot was adjusted to match the center size of the RF. Ganglion cells were dark adapted for 40 minutes before entering the sensitivity test. The luminance intensity at the retinal surface without neutral density filters ranged from 0.08 to 0.69 cd/m2 and background was 0.01 cd/m 2 . The intensity was attenuated with a set of neutral-density filters with 0.1 to 4 log units of attenuation. For each intensity, four trials were performed. Each trial consisted of eight circles, and each circle lasted for 2 seconds. Error bars, SE. The threshold luminance of wt RCS rats is used as control. Number of cells in each age group: congenic wt (n = 7, SEM = 0.75); P28–30 (n = 15, SEM = 0.21); P36–37 (n = 8, SEM = 0.49), P47–48 (n = 8, SEM = 57); P60–67 (n = 5, SEM = 69). P76 (n = 4, SEM = 61), P107–108 (n = 7, SEM = 42).
Figure 6.
 
Spatial frequency tuning curves for ganglion cells recorded from congenic wt and dystrophic RCS rats. Ganglion cells responded to a sinusoidal contrast grating drifted across the RF. Spatial frequency of the grating was within a degree of visual angle (cyc/deg). The temporal frequency of the grating was held constant at 1 Hz; contrast was 100%; average luminance on retinal surface 0.3 cd/m2. Response amplitudes shown represent the normalized average magnitude of the first harmonic component of the Fourier decomposition. Note the sudden decreases in response amplitudes at low spatial frequencies in P47–48 and P60–67 animals. Ganglion cells recorded from P76 animals did not respond to any spatial frequency of the grating. Symbols denote different age groups: ○, congenic wt; □, 28–30; Δ, 47–48; ×, 60–67; *, 76.
Figure 6.
 
Spatial frequency tuning curves for ganglion cells recorded from congenic wt and dystrophic RCS rats. Ganglion cells responded to a sinusoidal contrast grating drifted across the RF. Spatial frequency of the grating was within a degree of visual angle (cyc/deg). The temporal frequency of the grating was held constant at 1 Hz; contrast was 100%; average luminance on retinal surface 0.3 cd/m2. Response amplitudes shown represent the normalized average magnitude of the first harmonic component of the Fourier decomposition. Note the sudden decreases in response amplitudes at low spatial frequencies in P47–48 and P60–67 animals. Ganglion cells recorded from P76 animals did not respond to any spatial frequency of the grating. Symbols denote different age groups: ○, congenic wt; □, 28–30; Δ, 47–48; ×, 60–67; *, 76.
Figure 7.
 
Effect of grating contrast on response magnitude of ganglion cells recorded in vitro. Ganglion cells responded to a grating of 0.07 cyc/deg drifted at a fixed temporal frequency (1 Hz). Response amplitude represents the normalized average magnitude of the first harmonic component of the Fourier decomposition. Note the reduced response amplitudes at 100% contrast in P47–49 and P60-P67 animals and little contrast response left in P76 animals. Symbols depict the same age groups as in Figure 6 .
Figure 7.
 
Effect of grating contrast on response magnitude of ganglion cells recorded in vitro. Ganglion cells responded to a grating of 0.07 cyc/deg drifted at a fixed temporal frequency (1 Hz). Response amplitude represents the normalized average magnitude of the first harmonic component of the Fourier decomposition. Note the reduced response amplitudes at 100% contrast in P47–49 and P60-P67 animals and little contrast response left in P76 animals. Symbols depict the same age groups as in Figure 6 .
Table 1.
 
Luminance Threshold
Table 1.
 
Luminance Threshold
Age (PN Days) ON-Center OFF-Center
Cells (n) Mean Lum. (cd/m2) SD Cells (n) Mean Lum. (cd/m2) SD
28–30 7 −2.23 0.41 8 −2.48 0.55
36–37 3 −2.08 0.97 5 −2.10 0.55
47–48 1 −1.40 0.00 7 −2.11 0.46
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