Abstract
While photoreceptor loss is the most devastating result of inherited retinal degenerations such as retinitis pigmentosa, inner retinal neurons also undergo significant alteration. Detailing these changes has become important as many vision restorative therapies target the remaining neurons. In this study, the rd1-Fos-Tau-LacZ (rd1-FTL) mouse model was used to explore inner retinal change at a late stage of retinal degeneration, after the loss of photoreceptor nuclei. The rd1-FTL model carries a mutation in the phosphodiesterase gene, Pde6b, and an axonally targeted transgenic beta galactosidase reporter system under the control of the c-fos promoter. Retinae of transgenic rd1-FTL mice and control FTL animals aged 2–12 months were processed for indirect fluorescence immunocytochemistry. At 2 months of age, a time when the majority of photoreceptor nuclei are lost, there was negligible c-fos reporter (FTL) expression, however, from 4 months, reporter expression was observed to increase within subpopulations of amacrine and ganglion cells within the central retina. These areas of inner retinal FTL expression coincided with regions that contained aberrant Müller cells. Specifically, these cells exhibited reduced glutamine synthetase and Kir4.1 immunolabelling, whilst showing evidence of proliferative gliosis (increased cyclinD1 and glial fibrillary acidic protein expression). These changes were limited to distinct regions where cone photoreceptor terminals were absent. Overall, these results highlight that distinct areas of the rd1-FTL central retina undergo significant glial alterations after cone photoreceptor loss. These areas coincide with up-regulation of the c-fos reporter in the inner retina, which may represent a change in neuronal function/plasticity. The rd1-FTL mouse is a useful model system to probe changes that occur in the inner retina at later stages of retinal degeneration.
Highlights
Over recent years there has been a surge of interest in vision restoring therapies that replace the function of dead or dying photoreceptors using a variety of genetic, electronic or transplantation methods (Busskamp et al, 2008; O’Brien et al, 2012)
Our results show that c-fos reporter (FTL) expression is upregulated in inner retinal neurons within discrete patches in the central retina from 4 months of age
Cone Loss Occurs in Regions of Glial Loss and Abnormality At late stages of retinal degeneration, phase 3 remodeling is characterized by marked anatomical changes that are thought c-fos is an intermediate early gene that is known to be regulated during cell death, altered neural function and neural plasticity
Summary
Over recent years there has been a surge of interest in vision restoring therapies that replace the function of dead or dying photoreceptors using a variety of genetic, electronic or transplantation methods (Busskamp et al, 2008; O’Brien et al, 2012) For any of these treatments to succeed, a basic requirement is that the circuitry of the inner retina remains functionally intact and capable of passing visual information to higher visual centers. A range of changes occur in both neurons and glial cells in animal models of inherited retinal degeneration, as well as humans with retinitis pigmentosa (RP) These changes are classified into three phases based on retinal anatomy (Jones and Marc, 2005); Phases 1 and 2 refer to the periods of rod photoreceptor and cone photoreceptor death, respectively, while phase 3 is characterized by major anatomical changes in the inner retina including re-wiring of neural processes and the formation of a glial seal that encases the remaining retina (Marc et al, 2003). As most vision restorative therapies will be employed after photoreceptor death, a greater understanding of the events that occur in phase 3 degeneration will assist in optimizing these therapeutic approaches
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