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.