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B. W. Jones, R. E. Marc, H. Terasaki, M. Kondo; Computational Molecular Phenotyping and Excitation Mapping in the P347L Rhodopsin Transgenic Rabbit Model of Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2986. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Practical large animal models of retinitis pigmentosa (RP) are rare. It is difficult to predict the progression of cone-sparing forms of RP from rodent studies because the cones are so small and usually die along with rods. In human RP however, transformed cones often outlive rods and partially prevent retinal remodeling (Marc et al. 2007 IOVS 48: 3364-3371). Our goal was to assess the dependence of retinal remodeling on cone survival in the transgenic rhodopsin P347L (Tg P347L) rabbit model of autosomal dominant RP.
Three adult Tg P347L rabbits (ages 3, 4, 10 months) were euthanized via intraperitoneal urethane, the eyes enucleated and retinas incubated in vitro for excitation mapping with 1-amino-4-guanidobutane (AGB). Ocular fragments were incubated 10 min at 35 deg C in oxygenated Ames-Hepes medium + 5 mM AGB with and without iGluR agonists (KA 50 uM, NMDA 1 mM), followed by conventional fixation in buffered aldehydes, embedding in exopy resins and serial sectioning at 200 nm (Marc RE 1999 JCN 407:47-64). Retinal neurons were classified by computational molecular phenotyping (CMP, Marc and Jones 2002 J Neurosci22:413-427) using an array of small molecule signatures (asparate, glutamate, glycine, glutamine, glutathione, GABA, taurine) with the addition of tyrosine hydroxylase, rhodopsin, LWS1 cone opsin, and CRALBP macromolecule signals. Electroretinography was also performed to assess the state of rod loss prior to tissue harvest.
As in human retina, progressive rod-specific degeneration in the Tg P347L rabbit leads, by 10 months, to complete loss of rods (and rod signaling) and extensive survival of extremely deconstructed cones. Importantly, even deconstructed survivor cones clearly prevent the onset of gross remodeling and, importantly, preserves iGluR-coupled signaling to horizontal and bipolar cells. But also similar to human retina, survivor bipolar cells show evidence of neurite sprouting and potential reprogramming by upregulation of IGluR expression.
Disease progresssion in the Tg P347L rabbit model closely tracks human disease, including the cone-mediated preservation of bipolar cell signaling and triggering of reprogramming. The relatively fast disease progression makes the Tg P347L rabbit a superior model for cell biological, progenitor cell transplantation and bionic prosthetic studies.
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