Ординатура / Офтальмология / Английские материалы / Retinal Degenerations biology, diagnostics, and therapeutics_Tombran-Tink, Barnstable_2007

day 35, the thickness of the ONL has decreased significantly. At this stage, many rod photoreceptors still have long OS. In contrast to animal models expressing mutations in rhodopsin (6,28,63), the RCS retina does not show abnormal localization of rhodopsin in rod cell bodies and terminals because the immunostaining of rhodopsin is concentrated in the rod outer segments. Therefore, delocalization of rhodopsin may not be the trigger of ectopic synaptogenesis.

Comparing the percentages of remaining cell bodies at different postnatal days, the number of rod bipolar cells decreases much slower than the number of rods. The results also indicate, despite the much slower rate of cone loss during the ages studied, the RCS retina remains rod dominated; for example, in the 35-d-old RCS retina, the rod to cone ratio is approx 8.6:1. At this stage of degeneration in RCS rat retinas, consistent with the loss of rods and cones, the band of terminals in the OPL stained by antisynaptophysin has thinned. The estimated number of labeled terminals is 62.4% of normal, indicating synaptic abnormalities in about one-third of the rod terminals. Similar to findings in P347L pigs and rd mice, most rod bipolar cell dendrites in a 35-d-old RCS retina are no longer erect but appear to extend laterally. When the RCS retina is double labeled with antisynaptophysin and anti-PKCα antibodies, the results indicate that some rod bipolar cell dendrites still penetrate the band of cone pedicles to terminate near the outer border of the OPL, where the rod spherules are located. Furthermore, when double labeled with antisynaptophysin and anticone transducin γ antibodies, only some of the terminals are double labeled, indicating the presence of synaptophysin in some of the surviving rods. These results suggest that in the 35-d-old RCS retina, many surviving rods and cones may still have functioning synapses.

Consistent with this view, the b-wave amplitude of a single-flash, mixed rod-cone ERG of the 35-d-old RCS rats is approx 25.5% that of the non-dystrophic rat. By 45 d, the averaged b-wave amplitude reduces to 15.3%, and by 55 d, only 7.2%, of the nondystrophic rat. Examination of 35-d-old RCS retinas by EM shows that a small number of surviving rods still have intact invaginating synapses from rod bipolar cell dendrites. Even in a 55-d-old RCS retina, 4 out of 88 rod terminals examined (4.6%) still have invaginating synapses. Therefore, functional and abnormal rod synapses co-exist in the degenerating RCS retina.

Of the 154 cone terminals examined in a 35-d-old RCS retina, 54 (35.1%) have ectopic synaptic contacts with rod bipolar cell dendrites; all of them are the flat contact type. Some rod bipolar cell dendrites could make flat contact synapses with two cone terminals simultaneously. In addition to the cone to rod bipolar cell ectopic synapses, there are abnormal flat contact synapses on some rod terminals; such flat-contact synapses at rod terminals are not observed in nondystrophic retinas and, therefore, are likely ectopic synaptic contacts with rod bipolar cell dendrites. As demonstrated by EM immunocytochemistry, PKCα-stained rod bipolar cell dendrites indeed make flat contact ectopic synapses with rod terminals. Of the 252 rod terminals counted in the 35-d- old RCS retina, 50 (19.8%) have flat-contact synapses with rod bipolar cell dendrites. Most of these rod terminals show signs of degeneration (64), lacking intact synaptic ribbons and triad structure.

Identification of ectopic synapses in the RCS rat supports the conclusion that ectopic synaptogenesis is a general consequence of photoreceptor degeneration; and this event

may take place independent of a particular disease-inducing cell-specific gene mutation. Furthermore, as shown in the RCS rat, rather than being a default developmental outcome, ectopic synapses involving rod and cone photoreceptors and rod bipolar cell dendrites are the results of “neural re-wiring,” as a consequence of mutation-induced photoreceptor loss.

SYNAPTIC REMODELING IN OTHER RETINAL DEGENERATION ANIMAL MODELS AND THE UNDERLYING PRINCIPLES

OF SYNAPTIC PARTNERING IN THE RETINA

The aggregate of published results from studying ectopic synaptogenesis in a variety of RP animal models, from different species (and with mutations in different genes), including the P347L transgenic pig (rhodopsin), the rd mouse (PDE6B), and the RCS rat (Mertk), strongly suggests that the phenomenon is a common feature (downstream event) of mutation-induced retinal degeneration. Additional results from our laboratory further support this view. For example, in rhodopsin P347L transgenic mice, which express the same porcine rhodopsin P347L transgene as the P347L transgenic pig, EM analysis of anti-PKCα labeling has revealed similar cone to rod bipolar cell synapses (Fig. 3). Parallel experiments performed on analogous models, such as mice and pigs each expressing the porcine rhodopsin P347S transgene, have led to the same conclusion. Our preliminary studies of a rod-cone dysplasia 1 (rcd1) dog, which like the rd mouse, has a mutation in the PDE6B gene (65), have yielded results that support the notion that ectopic synaptogenesis occurs during degeneration in this animal model as well (Peng and Wong, unpublished results).

From the standpoint of potential postdeafferentation responses of the rod bipolar cells, which may include protein redistribution, synaptic remodeling, and degeneration, ectopic synaptogenesis involving cones and rod bipolar cells in the degenerating retina are certainly consistent with the expectations of general neuronal behavior (66–69).

As it was pointed out previously (6), formation of abnormal cone-to-rod bipolar cell synapses in animal models of mutation-induced photoreceptor degeneration demonstrates that the rod bipolar cell dendrites have the capability to make alternative connections when the preferred contacts are apparently not available. Hence, the rules that govern synaptic partnering between rods and rod bipolar cells and between cones and cone bipolar cells are not absolute; furthermore, the molecular mechanisms used by rods and cones to choose their synaptic partners share some common features. These concepts of the principles underlying synaptic partnering in the retina have been illustrated in a different context by a study of the neural retina leucine zipper (Nrl) gene knock out (KO) mice. In these mice, the rods fail to form developmentally and hence all the photoreceptors are cones (70). In these cone-only retinas, the rod bipolar cells form synaptic connections with cones (71). Accordingly, it seems that the principles guiding the formation of photoreceptor and bipolar cell synapses in the retina, as illustrated in the Nrl KO mouse, would predict ectopic synaptogenesis in degenerating retinas just as we have previously reported.

From these premises, it is a small leap of faith to hypothesize that even though there may not be any remaining rods, the residual rod-mediated signaling pathway persists and functions in the diseased retina. Although direct evidence is still lacking, the

Fig. 3. Electron micrograph of a 10-wk-old P347L transgenic mouse retina immunostained with PKCα antibody. Asterisk marks a labeled rod bipolar cell dendritic tip making ectopic synapse with a cone pedicle (CP). (B) Shows the higher magnification of the ectopic synaptic contact (arrowheads) in (A). Arrows indicate synaptic ribbon. Bar = 0.5 µm (A) and 0.1 µm (B).

collective morphological evidence and the indirect evidence summarized in this chapter are consistent with this hypothesis, e.g., ERG in the P347L transgenic pigs and lightinduced changes in PKCα-ir detected by monoclonal antibody Ab-2 in rod bipolar cells of the degenerated rd retina. Furthermore, even though the electron microscopic details

of the purported ectopic synapses have not been presented, morphological evidence collected at the light microscopic level and the parallel ERG analysis conducted in the rhodopsin P23H transgenic rat by Cuenca et al. (72) provide indirect evidence in support of the notion that after severe rod degeneration, the cone-mediated ERG has acquired a component that may result from cone input to the former rod-mediated signaling pathway. In short, in the rhodopsin P23H transgenic rat, just like in other animal models described in this chapter, ectopic cone-to-rod bipolar cell synapses may exist and via these synapses, the remaining cones may provide input to both the residual rod-mediated signaling pathway as well as the cone-mediated pathway.

IMPLICATIONS FOR PATHOGENESIS OF LATERAL EXTENSIONS OF ROD BIPOLAR CELL DENDRITES

It has been demonstrated a decade ago in the peripheral retina of specimens collected from patients with RP that rods extend long processes into the inner retina (73). These rod neurites usually bypass the OPL, where dendrites and processes of bipolar cells and horizontal cells—the usual synaptic targets of rod synaptic terminals—are located (56). Instead, the rod neurites extend to the INL and inner IPL, reaching even the inner limiting membrane. There is no evidence, however, suggesting that these rod neurites form any synapses with neurons in the inner retina (74); however, later studies reported presence of synaptic protein SV-2 ir in the terminals of these neurites, hinting at the potential presence of synaptic vesicles (75). In humans, such neurite sprouting is not observed in the macular region (73,74,76). Nonetheless, recently, Fei (77) has observed sprouting neurites from cones in the retinas of rd mice, starting from early stages of rod degeneration. Some of these sprouting neurites extend laterally and appear to make contacts with rod bipolar cell, although their synaptic fate is not known.

Rod bipolar cell dendrites undergo analogous “sprouting” under various conditions (78–80). Especially relevant to the topic under discussion is the lateral extensions of these dendrites in animal models of rod-cone degeneration. As illustrated in Fig. 4 (4-mo-old rd mouse) and Fig. 5 (9-mo-old P347S transgenic mouse), the dendrites of the rod bipolar cells extend laterally and make synapses with the terminals of neighboring cones. Furthermore, the rod bipolar cell soma have dislocated to the ONL. At the light microscopic level, the synaptic contacts appear to be on the cone cell bodies. Similar extensions of the rod bipolar cell dendrites have been documented independently by other investigators, e.g., in rd mouse81 and P23H transgenic rat (72).

The images presented in Figs. 4 and 5 suggest a scenario that the rod bipolar cell may actively initiate synaptic contacts with the surviving cones via its extensive dendritic tree. If the autonomous behavior of the rod bipolar cell dendrites is manifested very early, before extensive rod death, such action may in fact contribute to pathogenesis. For example, during the initial phase of rod death, when a few rod bipolar cell dendrites may have lost their synaptic input from the degenerated rods, the rod bipolar cell may withdraw some of its other dendrites from functioning rod-to-rod bipolar cell synapses. In so doing, the rod bipolar cell would accelerate the death of the rods. Morphological evidence consistent with such withdrawal by rod bipolar cell dendrites from functioning rod spherules indeed exists (82) and the speculative model of rod bipolar cell initiated rod death is currently under investigation.

Fig. 4. Cross sections at different focal planes obtained by confocal microscopy of a 4-mo-old rd mouse retina double-immunostained with PKCα and antisynaptophysin antibodies. Large arrows (1–4) indicate different remaining cone terminals (labeled with antisynaptophysin antibody in red) form ectopic synapses (yellow spots) with different rod bipolar cell dendrites (a–h, labeled with anti-PKCα antibody in green). Small arrows indicate extended rod bipolar cell dendrites. In this series of confocal images, it can be seen that a synaptophysin labeled cone terminal (large arrow 1 in panel A, red) makes synaptic contacts (yellow spots, small arrows in panels B, D, and E) with three different rod bipolar cells (a, b, and c, green), respectively. In panel D, rod bipolar cell b is seen extending its dendrite laterally to make synaptic contact (yellow spot, small arrow) with the cone terminal (red). In panel A, large arrow 2 indicates another synaptophysin labeled cone terminal (red) forming synaptic contact (yellow spot, small arrow) with the dendrite of rod bipolar cell d (green). The same cone terminal (large arrow 2) is contacted by rod bipolar cell e (small arrow in panel B). Analogous synaptic contacts between other cone terminals (arrows 3 and 4) and rod bipolar cells f, g, and h can be traced through the same series of potical sections. ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer. Scale bar = 50 µm.

Fig. 5. Cross section of a 9-mo-old P347S mouse retina double immunostained with antiPKCα (green) and antisynaptophysin (red) antibodies. Arrows indicate laterally extended rod bipolar cell dendrites. Arrowheads indicate dislocated rod bipolar cell somas in the ONL. These rod bipolar cells extended dendrites laterally toward the surviving synaptophysin labeled cone terminals (arrow, red). Labels as in Fig. 4.

CONCLUDING REMARKS

In this chapter, we have reviewed the discovery of ectopic synaptogenesis in several animal models of rod-cone degeneration. The major conclusions are: (1) ectopic synaptogenesis reflects a set of common downstream consequential events, triggered by a multitude of mutations that cause retinal degeneration; (2) ectopic synaptogenesis might occur early and could persist until the very late stages of degeneration; and (3) long after the death of rods, the residual rod-mediated signaling pathway persists and receives input from the surviving cones. The significance of the persistent anomalous wiring is not known.

We have restricted our discussions of synaptic remodeling to the OPL because what occurs in the inner retina, especially in the late stages of degeneration, has been reviewed by others (56). The “neuronal remodeling” or “negative cell remodeling” observed in the inner retina certainly would impact significantly some of the current theories regarding therapeutic approaches to treat patients in late stages of retinal degeneration. In parallel, retina-wide changes in the synaptic connections between photoreceptors and the second order neurons that occur early in the disease process, such as those summarized in this chapter, are expected to lead to more obvious and dramatic changes, including consequential events that would occur in the inner retina (83,84). In other words, early synaptic changes in the OPL and the changes in the inner retina observed at late stages of retinal degeneration may be causally related. Although this possibility remains to be investigated, the discovery of ectopic synaptogenesis has led us to a new hypothesis regarding the role of the rod bipolar cell in this phenomenon. Careful examination of the speculative model outlined in this chapter may lead us to a better understanding of the potential disease mechanisms underlying mutation-induced rod-cone degeneration.

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