Hostname: page-component-cd9895bd7-hc48f Total loading time: 0 Render date: 2024-12-26T07:13:55.400Z Has data issue: false hasContentIssue false
  • English
  • Français

Retinal morphological and functional changes in an animal model of retinitis pigmentosa

Published online by Cambridge University Press:  19 March 2013

BIN LU ,
CATHERINE W. MORGANS ,
SERGEY GIRMAN ,
RAYMOND LUND  and
SHAOMEI WANG
BIN LU
Affiliation:
Regenerative Medicine Institute, Department of Biomedical Science, Cedars-Sinai Medical Center, Los Angeles, California
CATHERINE W. MORGANS
Affiliation:
Department of Physiology & Pharmacology, OHSU, Portland, Oregon
SERGEY GIRMAN
Affiliation:
Regenerative Medicine Institute, Department of Biomedical Science, Cedars-Sinai Medical Center, Los Angeles, California
RAYMOND LUND
Affiliation:
Moran Eye Center, University of Utah, Salt Lake City, Utah
SHAOMEI WANG*
Affiliation:
Regenerative Medicine Institute, Department of Biomedical Science, Cedars-Sinai Medical Center, Los Angeles, California
*
*Address correspondence and reprint requests to: Shaomei Wang, Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048. E-mail: shaomei.wang@cshs.org
Get access Rights & Permissions [Opens in a new window]

Abstract

The P23H-1 transgenic rat carries a mutated mouse opsin gene, in addition to endogenous opsin genes, and undergoes progressive photoreceptor loss that is generally characteristic of human autosomal dominant retinitis pigmentosa (RP). Here, we examined morphological changes correlated with visual function that is comparable to clinical application in the pigmented P23H-1 rat retina as photoreceptor degeneration progressed. We found that rod function was compromised as early as postnatal day 28 and was a good indicator for tracking retinal degeneration. Cone function was normal and did not change until the thickness of the photoreceptor layer was reduced by 75%. Similar to the threshold versus intensity curves used to evaluate vision of RP patients, light-adaptation curves showed that cone thresholds depended on the number of remaining functioning cones, but not on its length of outer segments (OS). By 1 year of age, both rod and cone functions were significantly compromised. Correlating with early abnormal rod function, rods and related secondary neurons also underwent progressive degeneration, including shortening of inner and OS of photoreceptors, loss of rod bipolar and horizontal cell dendrites, thickening of the outer Müller cell processes, and reduced density of pre- and postsynaptic markers. Similar early morphological modifications were also observed in cones and their related secondary neurons. However, cone function was maintained at nearly normal level for a long period. The dramatic loss of rods at late stage of degeneration may contribute to the dysfunction of cones. Attention has to be focused on preserving cone function and identifying factors that damage cones when therapeutic regimes are applied to treat retinal degeneration. As such, these findings provide a foundation for future studies involving treatments to counter photoreceptor loss.

Keywords

P23H mutationRetinitis pigmentosaRetinal degenerationRod and coneVisual function
Type
Research Articles
Information
Visual Neuroscience , Volume 30 , Issue 3 , May 2013 , pp. 77 - 89
Copyright
Copyright © Cambridge University Press 2013 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Ambati, J., Anand, A., Fernandez, S., Sakurai, E., Lynn, B.C., Kuziel, W.A., Rollins, B.J. & Ambati, B.K. (2003). An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice. Nature Medicine 9, 1390–1397.CrossRefGoogle ScholarPubMed
Berson, E.L., Rosner, B., Sandberg, M.A. & Dryja, T.P. (1991 a). Ocular findings in patients with autosomal dominant retinitis pigmentosa and a rhodopsin gene defect (Pro-23-His). Archives of Ophthalmology 109, 92–101.CrossRefGoogle Scholar
Berson, E.L., Rosner, B., Sandberg, M.A., Weigel-DiFranco, C. & Dryja, T.P. (1991 b). Ocular findings in patients with autosomal dominant retinitis pigmentosa and rhodopsin, proline-347-leucine. American Journal of Ophthalmology 111, 614–623.CrossRefGoogle ScholarPubMed
Chang, B., Hawes, N.L., Hurd, R.E., Davisson, M.T., Nusinowitz, S. & Heckenlively, J.R. (2002). Retinal degeneration mutants in the mouse. Vision Research 42, 517–525.CrossRefGoogle ScholarPubMed
Chrysostomou, V., Stone, J., Stowe, S., Barnett, N.L. & Valter, K. (2008). The status of cones in the rhodopsin mutant P23H-3 retina: Light-regulated damage and repair in parallel with rods. Investigative Ophthalmology and Visual Science 49, 1116–1125.CrossRefGoogle ScholarPubMed
Chua, J., Fletcher, E.L. & Kalloniatis, M. (2009). Functional remodeling of glutamate receptors by inner retinal neurons occurs from an early stage of retinal degeneration. The Journal of Comparative Neurology 514, 473–491.CrossRefGoogle ScholarPubMed
Cuenca, N., Pinilla, I., Sauve, Y., Lu, B., Wang, S. & Lund, R.D. (2004). Regressive and reactive changes in the connectivity patterns of rod and cone pathways of P23H transgenic rat retina. Neuroscience 127, 301–317.CrossRefGoogle ScholarPubMed
D’Cruz, P.M., Yasumura, D., Weir, J., Matthes, M.T., Abderrahim, H., LaVail, M.M. & Vollrath, D. (2000). Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Human Molecular Genetics 9, 645–651.CrossRefGoogle ScholarPubMed
Dowling, J.E. & Sidman, R.L. (1962). Inherited retinal dystrophy in the rat. The Journal of Cell Biology 14, 73–107.CrossRefGoogle ScholarPubMed
Dryja, T.P., McGee, T.L., Hahn, L.B., Cowley, G.S., Olsson, J.E., Reichel, E., Sandberg, M.A. & Berson, E.L. (1990). Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa. Proceedings of the National Academy of Sciences of the United States of America 88, 9370–9374.CrossRefGoogle Scholar
Gamm, D.M., Wang, S., Lu, B., Girman, S., Holmes, T., Bischoff, N., Shearer, R.L., Sauve, Y., Capowski, E., Svendsen, C.N. & Lund, R.D. (2007). Protection of visual functions by human neural progenitors in a rat model of retinal disease. PLoS One 2, e338.CrossRefGoogle Scholar
Garcia-Ayuso, D., Salinas-Navarro, M., Agudo, M., Cuenca, N., Pinilla, I., Vidal-Sanz, M. & Villegas-Perez, M.P. (2010). Retinal ganglion cell numbers and delayed retinal ganglion cell death in the P23H rat retina. Experimental Eye Research 91, 800–810.CrossRefGoogle ScholarPubMed
Girman, S.V., Wang, S. & Lund, R.D. (2005). Time course of deterioration of rod and cone function in RCS rat and the effects of subretinal cell grafting: A light- and dark-adaptation study. Vision Research 45, 343–354.CrossRefGoogle ScholarPubMed
Harada, T., Harada, C., Nakayama, N., Okuyama, S., Yoshida, K., Kohsaka, S., Matsuda, H. & Wada, K. (2000). Modification of glial-neuronal cell interactions prevents photoreceptor apoptosis during light-induced retinal degeneration. Neuron 26, 533–541.CrossRefGoogle ScholarPubMed
Heckenlively, J.R., Rodriguez, J.A. & Daiger, S.P. (1991). Autosomal dominant sectoral retinitis pigmentosa. Two families with transversion mutation in codon 23 of rhodopsin. Archives of Ophthalmology 109, 84–91.CrossRefGoogle ScholarPubMed
Humayun, M.S., Prince, M., de Juan, E. Jr, Barron, Y., Moskowitz, M., Klock, I.B. & Milam, A.H. (1999). Morphometric analysis of the extramacular retina from postmortem eyes with retinitis pigmentosa. Investigative Ophthalmology and Visual Science 40, 143–148.Google ScholarPubMed
Humphries, M.M., Rancourt, D., Farrar, G.J., Kenna, P., Hazel, M., Bush, R.A., Sieving, P.A., Sheils, D.M., McNally, N., Creighton, P., Erven, A., Boros, A., Gulya, K., Capecchi, M.R. & Humphries, P. (1997). Retinopathy induced in mice by targeted disruption of the rhodopsin gene. Nature Genetics 15, 216–219.CrossRefGoogle ScholarPubMed
Jacobson, S.G., Voigt, W.J., Parel, J.M., Apathy, P.P., Nghiem-Phu, L., Myers, S.W. & Patella, V.M. (1986). Automated light- and dark-adapted perimetry for evaluating retinitis pigmentosa. Ophthalmology 93, 1604–1611.CrossRefGoogle ScholarPubMed
John, S.K., Smith, J.E., Aguirre, G.D. & Milam, A.H. (2000). Loss of cone molecular markers in rhodopsin-mutant human retinas with retinitis pigmentosa. Molecular Vision 6, 204–215.Google ScholarPubMed
Jones, B.W., Watt, C.B., Frederick, J.M., Baehr, W., Chen, C.K., Levine, E.M., Milam, A.H., Lavail, M.M. & Marc, R.E. (2003). Retinal remodeling triggered by photoreceptor degenerations. The Journal of Comparative Neurology 464, 1–16.CrossRefGoogle ScholarPubMed
Koulen, P., Fletcher, E.L., Craven, S.E., Bredt, D.S. & Wassle, H. (1998). Immunocytochemical localization of the postsynaptic density protein PSD-95 in the mammalian retina. Journal of Neuroscience 18, 10136–10149.CrossRefGoogle ScholarPubMed
Kwan, A.S., Wang, S. & Lund, R.D. (1999). Photoreceptor layer reconstruction in a rodent model of retinal degeneration. Experimental Neurology 159, 21–33.CrossRefGoogle Scholar
Lambard, S., Reichman, S., Berlinicke, C., Niepon, M.L., Goureau, O., Sahel, J.A., Leveillard, T. & Zack, D.J. (2010). Expression of rod-derived cone viability factor: Dual role of CRX in regulating promoter activity and cell-type specificity. PLoS One 5, e13075.CrossRefGoogle ScholarPubMed
Latch, M. & Lennie, P. (1977). Rod-cone interaction in light adaptation. The Journal of Physiology 269, 517–534.CrossRefGoogle ScholarPubMed
LaVail, M.M. (2001). Legacy of the RCS rat: Impact of a seminal study on retinal cell biology and retinal degenerative diseases. Progress in Brain Research 131, 617–627.CrossRefGoogle Scholar
Lawrence, J.M., Keegan, D.J., Muir, E.M., Coffey, P.J., Rogers, J.H., Wilby, M.J., Fawcett, J.W. & Lund, R.D. (2004). Transplantation of Schwann cell line clones secreting GDNF or BDNF into the retinas of dystrophic Royal College of Surgeons rats. Investigative Ophthalmology and Visual Science 45, 267–274.CrossRefGoogle ScholarPubMed
Lee, D.C., Vazquez-Chona, F.R., Ferrell, W.D., Tam, B.M., Jones, B.W., Marc, R.E. & Moritz, O.L. (2012). Dysmorphic photoreceptors in a P23H mutant rhodopsin model of retinitis pigmentosa are metabolically active and capable of regenerating to reverse retinal degeneration. Journal of Neuroscience 32, 2121–2128.CrossRefGoogle Scholar
Leonard, K.C., Petrin, D., Coupland, S.G., Baker, A.N., Leonard, B.C., LaCasse, E.C., Hauswirth, W.W., Korneluk, R.G. & Tsilfidis, C. (2007). XIAP protection of photoreceptors in animal models of retinitis pigmentosa. PLoS One 2, e314.CrossRefGoogle ScholarPubMed
Leveillard, T., Mohand-Said, S., Lorentz, O., Hicks, D., Fintz, A.C., Clerin, E., Simonutti, M., Forster, V., Cavusoglu, N., Chalmel, F., Dolle, P., Poch, O., Lambrou, G. & Sahel, J.A. (2004). Identification and characterization of rod-derived cone viability factor. Nature Genetics 36, 755–759.CrossRefGoogle ScholarPubMed
Leveillard, T. & Sahel, J.A. (2010). Rod-derived cone viability factor for treating blinding diseases: From clinic to redox signaling. Science Translational Medicine 2, 26ps16.CrossRefGoogle ScholarPubMed
Lewin, A.S., Drenser, K.A., Hauswirth, W.W., Nishikawa, S., Yasumura, D., Flannery, J.G. & LaVail, M.M. (1998). Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal dominant retinitis pigmentosa. Nature Medicine 4, 967–971.CrossRefGoogle Scholar
Li, L., Sheedlo, H.J. & Turner, J.E. (1993). Muller cell expression of glial fibrillary acidic protein (GFAP) in RPE-cell transplanted retinas of RCS dystrophic rats. Current Eye Research 12, 841–849.CrossRefGoogle ScholarPubMed
Lu, B., Malcuit, C., Wang, S., Girman, S., Francis, P., Lemieux, L., Lanza, R. & Lund, R. (2009). Long-term safety and function of RPE from human embryonic stem cells in preclinical models of macular degeneration. Stem Cells 27, 2126–2135.CrossRefGoogle ScholarPubMed
Lu, B., Wang, S., Girman, S., McGill, T., Ragaglia, V. & Lund, R. (2010). Human adult bone marrow-derived somatic cells rescue vision in a rodent model of retinal degeneration. Experimental Eye Research 91, 449–455.CrossRefGoogle Scholar
Machida, S., Kondo, M., Jamison, J.A., Khan, N.W., Kononen, L.T., Sugawara, T., Bush, R.A. & Sieving, P.A. (2000). P23H rhodopsin transgenic rat: Correlation of retinal function with histopathology. Investigative Ophthalmology and Visual Science 41, 3200–3209.Google ScholarPubMed
Machida, S., Raz-Prag, D., Fariss, R.N., Sieving, P.A. & Bush, R.A. (2008). Photopic ERG negative response from amacrine cell signaling in RCS rat retinal degeneration. Investigative Ophthalmology and Visual Science 49, 442–452.CrossRefGoogle ScholarPubMed
Marc, R.E., Jones, B.W., Anderson, J.R., Kinard, K., Marshak, D.W., Wilson, J.H., Wensel, T. & Lucas, R.J. (2007). Neural reprogramming in retinal degeneration. Investigative Ophthalmology and Visual Science 48, 3364–3371.CrossRefGoogle ScholarPubMed
Marc, R.E., Jones, B.W., Watt, C.B. & Strettoi, E. (2003). Neural remodeling in retinal degeneration. Progress in Retinal and Eye Research 22, 607–655.CrossRefGoogle ScholarPubMed
Milam, A.H., Li, Z.Y. & Fariss, R.N. (1998). Histopathology of the human retina in retinitis pigmentosa. Progress in Retinal and Eye Research 17, 175–205.Google ScholarPubMed
Nir, I. & Papermaster, D.S. (1989). Immunocytochemical localization of opsin in degenerating photoreceptors of RCS rats and rd and rds mice. Program in Clinical and Biological Research 314: 251–264.Google Scholar
Pignatelli, V., Cepko, C.L. & Strettoi, E. (2004). Inner retinal abnormalities in a mouse model of Leber’s congenital amaurosis. The Journal of Comparative Neurology 469, 351–359.CrossRefGoogle Scholar
Pittler, S.J. & Baehr, W. (1991). Identification of a nonsense mutation in the rod photoreceptor cGMP phosphodiesterase beta-subunit gene of the rd mouse. Proceedings of the National Academy of Sciences of the United States of America 88, 8322–8326.CrossRefGoogle ScholarPubMed
Ripps, H. (2002). Cell death in retinitis pigmentosa: Gap junctions and the ‘bystander’ effect. Experimental Eye Research 74, 327–336.CrossRefGoogle ScholarPubMed
Sandberg, M.A. & Berson, E.L. (1983). Visual acuity and cone spatial density in retinitis pigmentosa. Investigative Ophthalmology and Visual Science 24, 1511–1513.Google ScholarPubMed
Sandberg, M.A., Rosner, B., Weigel-DiFranco, C., McGee, T.L., Dryja, T.P. & Berson, E.L. (2008). Disease course in patients with autosomal recessive retinitis pigmentosa due to the USH2A gene. Investigative Ophthalmology and Visual Science 49, 5532–5539.CrossRefGoogle Scholar
Sheedlo, H.J., Jaynes, D., Bolan, A.L. & Turner, J.E. (1995). Mullerian glia in dystrophic rodent retinas: An immunocytochemical analysis. Brain Research. Developmental Brain Research 85, 171–180.CrossRefGoogle ScholarPubMed
Strettoi, E., Novelli, E., Mazzoni, F., Barone, I. & Damiani, D. (2010). Complexity of retinal cone bipolar cells. Progress in Retinal and Eye Research 29, 272–283.CrossRefGoogle ScholarPubMed
Strettoi, E. & Pignatelli, V. (2000). Modifications of retinal neurons in a mouse model of retinitis pigmentosa. Proceedings of the National Academy of Sciences of the United States of America 97, 11020–11025.CrossRefGoogle Scholar
Strettoi, E., Porciatti, V., Falsini, B., Pignatelli, V. & Rossi, C. (2002). Morphological and functional abnormalities in the inner retina of the rd/rd mouse. Journal of Neuroscience 22, 5492–5504.CrossRefGoogle ScholarPubMed
Sung, C.H., Davenport, C.M., Hennessey, J.C., Maumenee, I.H., Jacobson, S.G., Heckenlively, J.R., Nowakowski, R., Fishman, G., Gouras, P. & Nathans, J. (1991). Rhodopsin mutations in autosomal dominant retinitis pigmentosa. Proceedings of the National Academy of Sciences of the United States of America 88, 6481–6485.CrossRefGoogle ScholarPubMed
Vardi, N., Duvoisin, R., Wu, G. & Sterling, P. (2000). Localization of mGluR6 to dendrites of ON bipolar cells in primate retina. The Journal of Comparative Neurology 423, 402–412.3.0.CO;2-E>CrossRefGoogle Scholar
Vardi, N. & Morigiwa, K. (1997). ON cone bipolar cells in rat express the metabotropic receptor mGluR6. Visual Neuroscience 14, 789–794.CrossRefGoogle ScholarPubMed
Vardi, N., Morigiwa, K., Wang, T.L., Shi, Y.J. & Sterling, P. (1998). Neurochemistry of the mammalian cone ‘synaptic complex’. Vision Research 38, 1359–1369.CrossRefGoogle ScholarPubMed
Villegas-Perez, M.P., Lawrence, J.M., Vidal-Sanz, M., Lavail, M.M. & Lund, R.D. (1998). Ganglion cell loss in RCS rat retina: A result of compression of axons by contracting intraretinal vessels linked to the pigment epithelium. The Journal of Comparative Neurology 392, 58–77.3.0.CO;2-O>CrossRefGoogle Scholar
Wang, S., Lu, B., Girman, S., Holmes, T., Bischoff, N. & Lund, R.D. (2008). Morphological and functional rescue in RCS rats after RPE cell line transplantation at a later stage of degeneration. Investigative Ophthalmology and Visual Science 49, 416–421.CrossRefGoogle Scholar
Wang, S., Lu, B. & Lund, R.D. (2005 a). Morphological changes in the Royal College of Surgeons rat retina during photoreceptor degeneration and after cell-based therapy. The Journal of Comparative Neurology 491, 400–417.CrossRefGoogle ScholarPubMed
Wang, S., Lu, B., Wood, P. & Lund, R.D. (2005 b). Grafting of ARPE-19 and Schwann Cells to the subretinal space in RCS rats. Investigative Ophthalmology and Visual Science 46, 2552–2560.CrossRefGoogle Scholar
Wang, S., Villegas-Perez, M.P., Holmes, T., Lawrence, J.M., Vidal-Sanz, M., Hurtado-Montalban, N. & Lund, R.D. (2003). Evolving neurovascular relationships in the RCS rat with age. Current Eye Research 27, 183–196.CrossRefGoogle ScholarPubMed
Wang, S., Villegas-Perez, M.P., Vidal-Sanz, M. & Lund, R.D. (2000). Progressive optic axon dystrophy and vascular changes in rd mice. Investigative Ophthalmology and Visual Science 41, 537–545.Google ScholarPubMed
Wassle, H., Grunert, U., Chun, M.H. & Boycott, B.B. (1995). The rod pathway of the macaque monkey retina: Identification of AII-amacrine cells with antibodies against calretinin. The Journal of Comparative Neurology 361, 537–551.CrossRefGoogle ScholarPubMed
Wassle, H., Grunert, U. & Rohrenbeck, J. (1993). Immunocytochemical staining of AII-amacrine cells in the rat retina with antibodies against parvalbumin. The Journal of Comparative Neurology 332, 407–420.CrossRefGoogle ScholarPubMed
Westheimer, G. (1967). Spatial interaction in human cone vision. The Journal of Physiology 190, 139–154.CrossRefGoogle ScholarPubMed
Yang, Y., Mohand-Said, S., Leveillard, T., Fontaine, V., Simonutti, M. & Sahel, J.A (2010). Transplantation of photoreceptor and total neural retina preserves cone function in P23H rhodopsin transgenic rat. PLoS One 5, e13469.CrossRefGoogle ScholarPubMed
Zeiss, C.J. (2010). Animals as models of age-related macular degeneration: An imperfect measure of the truth. Veterinary Pathology 47, 396–413.CrossRefGoogle ScholarPubMed
Zhang, H., Cuenca, N., Ivanova, T., Church-Kopish, J., Frederick, J.M., MacLeish, P.R. & Baehr, W. (2003). Identification and light-dependent translocation of a cone-specific antigen, cone arrestin, recognized by monoclonal antibody 7G6. Investigative Ophthalmology and Visual Science 44, 2858–2867.CrossRefGoogle ScholarPubMed
Zhang, K., Kniazeva, M., Han, M., Li, W., Yu, Z., Yang, Z., Li, Y., Metzker, M.L., Allikmets, R., Zack, D.J., Kakuk, L.E., Lagali, P.S., Wong, P.W., MacDonald, I.M., Sieving, P.A., Figueroa, D.J., Austin, C.P., Gould, R.J., Ayyagari, R. & Petrukhin, K. (2001). A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nature Genetics 27, 89–93.CrossRefGoogle ScholarPubMed