Morphological alterations in retinal neurons in the S334ter-line3 transgenic rat

Abstract

The S334ter-line-3 rat is a transgenic model of retinal degeneration developed to express a rhodopsin mutation similar to that found in human retinitis pigmentosa (RP) patients. Previous studies have focused on physiological changes in retinal cells and higher centers of the visual system with this model of retinal degeneration. However, little is known about the morphological changes in retinal cells during the development of the S334ter-line-3 rat. In order to understand and aid vision-rescue strategies, our aim has been to describe the retinal degeneration pattern in this model. We focus on changes in the morphologies of horizontal, bipolar, and amacrine cells in developing S334ter-line-3 rat retinas. Degeneration of photoreceptors begins in the central retina and progresses toward the periphery. In retinas at post-natal day 15 (P15), horizontal and rod bipolar cells show normal morphology. However, at P21, horizontal and rod bipolar cells exhibit abnormal processes at the outer plexiform layer, whereas the outer nuclear layer is significantly thinner. A glial reaction occurs concomitantly. In contrast, modifications in cone-bipolar and amacrine cells are much slower and do not occur until P90 and P180, respectively. The density of horizontal and rod-bipolar cells significantly drops after P60. Overall, the S334ter-line-3 model exhibits the hallmarks of cellular remodeling caused by photoreceptor degeneration. Its moderately fast time course makes the S334ter-line-3 a good model for studying vision-rescue strategies.

Role of Müller cells in cone mosaic rearrangement in a rat model of retinitis pigmentosa

“…2E). Such clusters were consistent with our previous study showing massive rod cell death around P15 (Ray et al, 2010). Hence, the holes emerged at least in part because of clusters of rod death.…”

“…2). Previous studies examined rod cell deaths in the vertical sections of homozygous (Li et al, 2010) and heterozygous animals of S334ter-line-3 rat retinas (Liu et al, 1999;Martinez-Navarrete et al, 2010;Ray et al, 2010;Sagdullaev et al, 2003). Vertical-section studies only allow us to look at the thickness of the ONL and to observe how it decreases as the disease progresses.…”

“…In addition, M€ uller cells are one of the main cell types involved in the formation of subretinal cellular membranes (Lewis et al, 1994). In detached and retinal-degeneration retinas, M€ uller cells begin to hypertrophy, filling the space left by dying photoreceptors, and then grow along the exposed outer surface of the retina (Gargini et al, 2007;Lewis et al, 1994;Lewis and Fisher, 2000;Marc and Jones, 2003;Ray et al, 2010). Such remodeling is not surprising, as M€ uller cells contain trophic receptors for most of the molecules involved in photoreceptor rescue (Bringmann et al, 2006;Harada et al, 1995;Wen et al, 1995).…”

“…Our RP model also showed such upregulation of GFAP by M€ uller cells (Ray et al, 2010). To examine whether GFAP followed the remodeled processes of M€ uller cells, we performed double labeling of GS (Fig.…”

“…The primary pathological event of this disease is the death of rods because of genetic mutations. Studies in animal models of RP have shown that rod degeneration leads to cone (Li et al, 2010;Lin et al, 2009) and inner-retinal (Gargini et al, 2007;Jones and Marc, 2005;Marc and Jones, 2003;Martinez-Navarrete et al, 2010;Ray et al, 2010;Strettoi et al, 2004) remodeling, resulting in abnormal circuitry. In addition, rod degeneration frequently results in the death of cones, although the extent of their apoptosis varies across patients (Hartong et al, 2006;Ripps, 2002) and animal models (Carter-Dawson et al, 1978;Jimenez et al, 1996;LaVail et al, 1998).…”