Inner retinal abnormalities in a mouse model of Leber's congenital amaurosis

Abstract

Leber's congenital amaurosis (LCA) is the earliest and most severe form in the world of genetic retinal dystrophy causing blindness. An animal model of LCA was recently created in which the cone-rod homeobox (crx) gene was disrupted using homologous recombination. Crx-/- mice display abnormal development of photoreceptors followed by their degeneration. We analyzed the morphology of inner retinal cells in crx-/- mice in order to evaluate the effects of abnormal photoreceptor development and death upon other retinal neurons. The identification of a time window during which inner retinal cells are still viable could be very important in view of the possibilities that photoreceptor transplantation or gene therapy might be used to restore vision in LCA. We used a combination of immunocytochemical and confocal microscopy techniques to screen the crx-/- inner retina and verify its morphological integrity after photoreceptor degeneration. We found significant morphological alterations in second-order neurons in crx-/- animals. The appearance of mutant retinas after photoreceptor death is indistinguishable from that of the retinal degeneration (rd/rd) mouse, a different genetic model of a retinal disease characterized by photoreceptor degeneration. However, at early stages of photoreceptor degeneration the morphology of retinal cells in the crx-/- mutant is considerably well preserved. It is likely that different genetic mechanisms that cause abnormal photoreceptor development and/or degeneration lead to a common pathway that determines second-order neuron modifications. The severity of modifications is linked to the timing of onset of the degeneration and appears to increase with time.

Intravitreal injection of ciliary neurotrophic factor (CNTF) causes peripheral remodeling and does not prevent photoreceptor loss in canine RPGR mutant retina

“…Retinal remodeling associated with photorececeptor degeneration as been reported by several groups in humans with RP (Fariss et al, 2000;Jones et al, 2003), as well as in animal models (Strettoi and Pignatelli, 2000;Fisher and Lewis, 2003;Marc et al, 2003;Pignatelli et al, 2004;Jones et al, 2005;Beltran et al, 2006). In this study, a striking finding was the prominent remodeling that occurred in the peripheral retina of XLPRA2 dogs following intravitreal injection of CNTF.…”

Inner retinal photoreception independent of the visual retinoid cycle

“…In addition to direct effects on photoreceptors, the rd͞rd mutation also results in alterations in inner retinal circuitry (32)(33)(34). Similar changes have also been reported in retinas of mice with mutations in the Leber's congenital amaurosis-causing gene Crx (35) and after simple visual deprivation (36,37). Recently, acute outer retinal degeneration has been reported to alter melanopsin expression levels in the inner retina of the rat (38,39).…”

Preservation of outer retina and its synaptic connectivity following subretinal injections of human RPE cells in the Royal College of Surgeons rat

“…Previous work (Peng et al, 2003) has indicated that the rod bipolar cells might in fact receive ectopic input from remaining cone photoreceptors. While there is indication that with time there are substantial changes in inner retinal organization , Marc et al, 2003, Pignatelli et al, 2004, which may in part be the result of vascular pathology (Villegas-Pérez et al, 1998) but which has little to say for the early detailed circuit reorganization during the time course studied here.…”