Abstract
In rodents and felines, intravitreal administration of adenosine triphosphate (ATP) has been shown to induce photoreceptor death providing a tractable model of retinal degeneration in these species. This study investigated the long term effects of photoreceptor loss in an ATP induced feline model of retinal degeneration. Six normal sighted felines were unilaterally blinded using intravitreal ATP injections and assessed using electroretinography (ERG) and optical coherence tomography (OCT). At 30 h (n = 3) or 12 weeks (n = 3) post-injection, the animals were euthanized and the eyes enucleated. Retinae were sectioned and labeled using immunohistochemistry for markers of cell death, neural remodeling and gliosis. Ongoing cell death and retinal degeneration was observed in the outer retina at both 30 h and 12 weeks following unilateral ATP injection. Markers of mid to late-stage retinal remodeling such as cell displacement and aberrant neurite growth were observed in the inner retina at 12 weeks post-injection. Ganglion cells appeared to remain intact in ATP injected eyes. Müller cell gliosis was observed throughout the inner and outer retina, in some parts completely enveloping and/or displacing the surviving neural tissue. Our data suggests that the ATP injected feline retina continues to undergo progressive retinal degeneration and exhibits abnormalities consistent with a description of retinal remodeling commonly seen in other models of retinal degeneration. These findings validate the use of intravitreal ATP injection in feline as a large animal model of retinal degeneration which may aid in development of therapies aiming to restore visual function after photoreceptor degeneration.
Highlights
Retinitis pigmentosa (RP) is an inherited retinal dystrophy characterized by dysfunction and progressive loss of rod and/or cone photoreceptors in the retina
We previously developed a feline model of retinal degeneration using unilateral adenosine triphosphate (ATP) injection, which lead to rapid photoreceptor cell death followed by progressive degeneration over a 12 week period (Aplin et al, 2014)
Given that severe loss and remodeling of the outer nuclear layer (ONL) would be expected to lead to remodeling of inner retinal processes, we examined the effect of ATP-induced chronic photoreceptor degeneration on bipolar cells and synapses in the inner nuclear layer (INL) and OPL/IPL
Summary
Retinitis pigmentosa (RP) is an inherited retinal dystrophy characterized by dysfunction and progressive loss of rod and/or cone photoreceptors in the retina. The need for safe, rapid and effective large eyed animal models of retinal disease has intensified as we move to an era of restorative strategies such as neural prostheses, optogenetics and photoreceptor sheet transplantation (Dahlmann-Noor et al, 2010; O’Brien et al, 2012; Seiler and Aramant, 2012; Shepherd et al, 2013; Singh et al, 2013; Zrenner, 2013) as well as stem cell and gene replacement therapies (Limb and Daniels, 2008; Dahlmann-Noor et al, 2010). In order to maximize the potential for restoration of vision in disease of photoreceptors, a large animal model must recapitulate the degenerative process observed in humans, including and importantly the inner retinal neurons, especially the ganglion cells, which must remain intact and capable of passing information to higher centers. Even after successful clinical application of a new technology, animal models remain relevant as they enable researchers to better understand the impact of primary and secondary degenerative processes on optimal device or treatment performance (Bertschinger et al, 2008)
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