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Japanese Journal of Ophthalmology

, Volume 60, Issue 2, pp 111–125 | Cite as

Changes in morphology and visual function over time in mouse models of retinal degeneration: an SD-OCT, histology, and electroretinography study

  • Tomoko Hasegawa
  • Hanako O. IkedaEmail author
  • Noriko Nakano
  • Yuki Muraoka
  • Tatsuaki Tsuruyama
  • Keiko Okamoto-Furuta
  • Haruyasu Kohda
  • Nagahisa Yoshimura
Laboratory Investigation

Abstract

Purpose

To examine the long-term natural course of retinal degeneration in rd10 and rd12 mice using serial spectral-domain optical coherence tomography (SD-OCT), electroretinography/electroretinograms (ERGs), and histological analysis.

Methods

Photoreceptor layer thickness and the ability to visualize photoreceptor ellipsoid zones were analyzed using SD-OCT images, and these images were compared with hematoxylin and eosin-stained sections and electron microscopy images. The a- and b-wave amplitudes of the ERGs were analyzed.

Results

In rd10 mice, the photoreceptor layer thickness rapidly decreased, and the photoreceptor ellipsoid zone was visible on SD-OCT images in 89 and 43 % of eyes of 21 and 33-day-old mice, respectively. In rd12 mice, the photoreceptor layer gradually thinned, and the ellipsoid zone remained visible in 92 % of eyes at 19 months. Electron microscopy revealed that photoreceptor degeneration had occurred on the inner side of the outer nuclear layer in 21-day-old rd10 and 7-month-old rd12 mice, possibly due to autophagy mechanisms. Scotopic ERGs of rd10 mice showed a diminished response at 21 days; at 33 days, no response was detectable. In rd12 mice, scotopic ERGs were undetectable at 28 days (stimulus intensity 3.0 cds/m2). Photopic ERGs were nearly undetectable in 28-day-old rd10 mice, but a small b-wave was still recordable in 13-month-old rd12 mice.

Conclusions

Our results demonstrate that visual function deteriorated with photoreceptor degeneration within 1 month in rd10 mice. In rd12 mice, however, the process of visual function deterioration and photoreceptor degeneration was still in progress at 13 months of age.

Keywords

rd10 rd12 Retinal degeneration Longitudinal study Spectral-domain optical coherence tomography 

Notes

Acknowledgments

We thank Hitomi Suetsugu for technical assistance and the Center for Anatomical, Pathological, and Forensic Medical Research for preparation of the histological sections. This study was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Grand-in-Aid for Young Scientists No. 24791850 and for the Innovative Techno-Hub for Integrated Medical Bio-Imaging of the Project for Developing Innovation Systems No. 24249082). This study was also supported by grants from the Ministry of Health, Labour and Welfare of Japan and Japan Society for the Promotion of Science.

Conflicts of interest

T. Hasegawa, none; H.O. Ikeda, Grant (the Astellas Foundation for Research on Metabolic Disorders, the Japan Foundation for Applied Enzymology, the Uehara Memorial Foundation, YOKOYAMA Foundation for Clinical Pharmacology, Mochida Memorial Foundation, Japan Intractable Diseases Research Foundation, Japan Research Foundation for Clinical Pharmacology); N. Nakano, none; Y. Muraoka, none; T. Tsuruyama, None; K. O. Furuta, none; H. Kohda, none; N. Yoshimura, grant (Nidek, Topcon, Canon, Novartis Japan, Bayer, Santen, Senju), honorary (Nidek, Canon, Novartis Japan, Bayer, Santen, Senju), and consultant fee (Nidek, Canon).

Supplementary material

10384_2015_422_MOESM1_ESM.pdf (214 kb)
Supplementary material 1 (PDF 213 kb)

References

  1. 1.
    Shintani K, Shechtman DL, Gurwood AS. Review and update: current treatment trends for patients with retinitis pigmentosa. Optometry. 2009;80:384–401.CrossRefPubMedGoogle Scholar
  2. 2.
    Ng TK, Fortino VR, Pelaez D, Cheung HS. Progress of mesenchymal stem cell therapy for neural and retinal diseases. World J Stem Cells. 2014;6:111–9.PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Acland GM, Aguirre GD, Ray J, Zhang Q, Aleman TS, Cideciyan AV, et al. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet. 2001;28:92–5.PubMedGoogle Scholar
  4. 4.
    Cai X, Conley SM, Naash MI. RPE65: role in the visual cycle, human retinal disease, and gene therapy. Ophthalmic Genet. 2009;30:57–62.PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Sieving PA, Caruso RC, Tao W, Coleman HR, Thompson DJ, Fullmer KR, et al. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc Natl Acad Sci USA. 2006;103:3896–901.PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Yang PB, Seiler MJ, Aramant RB, Yan F, Mahoney MJ, Kitzes LM, et al. Trophic factors GDNF and BDNF improve function of retinal sheet transplants. Exp Eye Res. 2010;91:727–38.PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Yang Y, Mohand-Said S, Danan A, Simonutti M, Fontaine V, Clerin E, et al. Functional cone rescue by RdCVF protein in a dominant model of retinitis pigmentosa. Mol Ther. 2009;17:787–95.PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Chizzolini M, Galan A, Milan E, Sebastiani A, Costagliola C, Parmeggiani F. Good epidemiologic practice in retinitis pigmentosa: from phenotyping to biobanking. Curr Genomics. 2011;12:260–6.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet. 2006;368:1795–809.CrossRefPubMedGoogle Scholar
  10. 10.
    Oishi M, Oishi A, Gotoh N, Ogino K, Higasa K, Iida K, et al. Comprehensive molecular diagnosis of a large cohort of Japanese retinitis pigmentosa and usher syndrome patients by next-generation sequencing. Invest Ophthalmol Vis Sci. 2014;55:7369–75.CrossRefPubMedGoogle Scholar
  11. 11.
    den Hollander AI, Roepman R, Koenekoop RK, Cremers FP. Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res. 2008;27:391–419.CrossRefGoogle Scholar
  12. 12.
    Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, et al. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med. 2008;358:2231–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Bennett J, Ashtari M, Wellman J, Marshall KA, Cyckowski LL, Chung DC, et al. AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med. 2012;4:120ra15.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F, Bennicelli J, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med. 2008;358:2240–8.PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Chang B, Hawes NL, Pardue MT, German AM, Hurd RE, Davisson MT, et al. Two mouse retinal degenerations caused by missense mutations in the beta-subunit of rod cGMP phosphodiesterase gene. Vis Res. 2007;47:624–33.PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Rivas MA, Vecino E. Animal models and different therapies for treatment of retinitis pigmentosa. Histol Histopathol. 2009;24:1295–322.PubMedGoogle Scholar
  17. 17.
    Pang JJ, Chang B, Hawes NL, Hurd RE, Davisson MT, Li J, et al. Retinal degeneration 12 (rd12): a new, spontaneously arising mouse model for human Leber congenital amaurosis (LCA). Mol Vis. 2005;11:152–62.PubMedGoogle Scholar
  18. 18.
    Redmond TM, Yu S, Lee E, Bok D, Hamasaki D, Chen N, et al. Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle. Nat Genet. 1998;20:344–51.CrossRefPubMedGoogle Scholar
  19. 19.
    Zheng Q, Ren Y, Tzekov R, Zhang Y, Chen B, Hou J, et al. Differential proteomics and functional research following gene therapy in a mouse model of Leber congenital amaurosis. PLoS ONE. 2012;7:e44855.PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Huang D, Swanson EA, Lin CP, Schuman JS, Stinson WG, Chang W, et al. Optical coherence tomography. Science. 1991;254:1178–81.PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Jaffe GJ, Caprioli J. Optical coherence tomography to detect and manage retinal disease and glaucoma. Am J Ophthalmol. 2004;137:156–69.CrossRefPubMedGoogle Scholar
  22. 22.
    Hangai M, Yamamoto M, Sakamoto A, Yoshimura N. Ultrahigh-resolution versus speckle noise-reduction in spectral-domain optical coherence tomography. Opt Express. 2009;17:4221–35.CrossRefPubMedGoogle Scholar
  23. 23.
    Huber G, Beck SC, Grimm C, Sahaboglu-Tekgoz A, Paquet-Durand F, Wenzel A, et al. Spectral domain optical coherence tomography in mouse models of retinal degeneration. Invest Ophthalmol Vis Sci. 2009;50:5888–95.PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Kim KH, Puoris’haag M, Maguluri GN, Umino Y, Cusato K, Barlow RB, et al. Monitoring mouse retinal degeneration with high-resolution spectral-domain optical coherence tomography. J Vis. 2008;8:17.1–17.11.CrossRefGoogle Scholar
  25. 25.
    Pang JJ, Dai X, Boye SE, Barone I, Boye SL, Mao S, et al. Long-term retinal function and structure rescue using capsid mutant AAV8 vector in the rd10 mouse, a model of recessive retinitis pigmentosa. Mol Ther. 2011;19:234–42.PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Pennesi ME, Michaels KV, Magee SS, Maricle A, Davin SP, Garg AK, et al. Long-term characterization of retinal degeneration in rd1 and rd10 mice using spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci. 2012;53:4644–56.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Ruggeri M, Wehbe H, Jiao S, Gregori G, Jockovich ME, Hackam A, et al. In vivo three-dimensional high-resolution imaging of rodent retina with spectral-domain optical coherence tomography. Invest Ophthalmol Vis Sci. 2007;48:1808–14.CrossRefPubMedGoogle Scholar
  28. 28.
    Wang R, Jiang C, Ma J, Young MJ. Monitoring morphological changes in the retina of rhodopsin-/- mice with spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci. 2012;53:3967–72.CrossRefPubMedGoogle Scholar
  29. 29.
    Nakano N, Ikeda HO, Hangai M, Muraoka Y, Toda Y, Kakizuka A, et al. Longitudinal and simultaneous imaging of retinal ganglion cells and inner retinal layers in a mouse model of glaucoma induced by N-methyl-d-aspartate. Invest Ophthalmol Vis Sci. 2011;52:8754–62.CrossRefPubMedGoogle Scholar
  30. 30.
    Muraoka Y, Ikeda HO, Nakano N, Hangai M, Toda Y, Okamoto-Furuta K, et al. Real-time imaging of rabbit retina with retinal degeneration by using spectral-domain optical coherence tomography. PLoS ONE. 2012;7:e36135.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Marmor MF, Fulton AB, Holder GE, Miyake Y, Brigell M, Bach M. ISCEV standard for full-field clinical electroretinography (2008 update). Doc Ophthalmol. 2009;118:69–77.CrossRefPubMedGoogle Scholar
  32. 32.
    Staurenghi G, Sadda S, Chakravarthy U, Spaide RF. Proposed lexicon for anatomic landmarks in normal posterior segment spectral-domain optical coherence tomography: the IN*OCT consensus. Ophthalmology. 2014;121:1572–8.CrossRefPubMedGoogle Scholar
  33. 33.
    Wong IY, Iu LP, Koizumi H, Lai WW. The inner segment/outer segment junction: what have we learnt so far? Curr Opin Ophthalmol. 2012;23:210–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Oishi A, Hata M, Shimozono M, Mandai M, Nishida A, Kurimoto Y. The significance of external limiting membrane status for visual acuity in age-related macular degeneration. Am J Ophthalmol. 2010;150(27–32):e1.PubMedGoogle Scholar
  35. 35.
    Breton ME, Schueller AW, Lamb TD, Pugh EN Jr. Analysis of ERG a-wave amplification and kinetics in terms of the G-protein cascade of phototransduction. Invest Ophthalmol Vis Sci. 1994;35:295–309.PubMedGoogle Scholar
  36. 36.
    Hood DC, Birch DG. Beta wave of the scotopic (rod) electroretinogram as a measure of the activity of human on-bipolar cells. J Opt Soc Am A Opt Image Sci Vis. 1996;13:623–33.CrossRefPubMedGoogle Scholar
  37. 37.
    Korol S, Leuenberger PM, Englert U, Babel J. In vivo effects of glycine on retinal ultrastructure and averaged electroretinogram. Brain Res. 1975;97:235–51.CrossRefPubMedGoogle Scholar
  38. 38.
    Jacobson SG, Aleman TS, Cideciyan AV, Sumaroka A, Schwartz SB, Windsor EA, et al. Identifying photoreceptors in blind eyes caused by RPE65 mutations: prerequisite for human gene therapy success. Proc Natl Acad Sci USA. 2005;102:6177–82.PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    Seeliger MW, Grimm C, Stahlberg F, Friedburg C, Jaissle G, Zrenner E, et al. New views on RPE65 deficiency: the rod system is the source of vision in a mouse model of Leber congenital amaurosis. Nat Genet. 2001;29:70–4.CrossRefPubMedGoogle Scholar
  40. 40.
    Kuroda M, Hirami Y, Hata M, Mandai M, Takahashi M, Kurimoto Y. Intraretinal hyperreflective foci on spectral-domain optical coherence tomographic images of patients with retinitis pigmentosa. Clin Ophthalmol. 2014;8:435–40.PubMedCentralCrossRefPubMedGoogle Scholar
  41. 41.
    Bo Q, Ma S, Han Q, Wang FE, Li X, Zhang Y. Role of autophagy in photoreceptor cell survival and death. Crit Rev Eukaryot Gene Expr. 2015;25:23–32.CrossRefPubMedGoogle Scholar
  42. 42.
    Sancho-Pelluz J, Arango-Gonzalez B, Kustermann S, Romero FJ, van Veen T, Zrenner E, et al. Photoreceptor cell death mechanisms in inherited retinal degeneration. Mol Neurobiol. 2008;38:253–69.CrossRefPubMedGoogle Scholar
  43. 43.
    Newsome DA, Michels RG. Detection of lymphocytes in the vitreous gel of patients with retinitis pigmentosa. Am J Ophthalmol. 1988;105:596–602.CrossRefPubMedGoogle Scholar
  44. 44.
    Yoshida N, Ikeda Y, Notomi S, Ishikawa K, Murakami Y, Hisatomi T, et al. Clinical evidence of sustained chronic inflammatory reaction in retinitis pigmentosa. Ophthalmology. 2013;120:100–5.CrossRefPubMedGoogle Scholar
  45. 45.
    Yoshida N, Ikeda Y, Notomi S, Ishikawa K, Murakami Y, Hisatomi T, et al. Laboratory evidence of sustained chronic inflammatory reaction in retinitis pigmentosa. Ophthalmology. 2013;120:e5–12.CrossRefPubMedGoogle Scholar
  46. 46.
    Sahel J, Bonnel S, Mrejen S, Paques M. Retinitis pigmentosa and other dystrophies. Dev Ophthalmol. 2010;47:160–7.CrossRefPubMedGoogle Scholar
  47. 47.
    Cunha-Vaz JG, Travassos A. Breakdown of the blood–retinal barriers and cystoid macular edema. Surv Ophthalmol. 1984;28:485–92.CrossRefPubMedGoogle Scholar
  48. 48.
    Fishman GA, Cunha-Vaz J, Salzano T. Vitreous fluorophotometry in patients with retinitis pigmentosa. Arch Ophthalmol. 1981;99:1202–7.CrossRefPubMedGoogle Scholar
  49. 49.
    Kuchle M, Nguyen NX, Martus P, Freissler K, Schalnus R. Aqueous flare in retinitis pigmentosa. Graefes Arch Clin Exp Ophthalmol. 1998;236:426–33.CrossRefPubMedGoogle Scholar
  50. 50.
    Vinores SA, Kuchle M, Derevjanik NL, Henderer JD, Mahlow J, Green WR, et al. Blood-retinal barrier breakdown in retinitis pigmentosa: light and electron microscopic immunolocalization. Histol Histopathol. 1995;10:913–23.PubMedGoogle Scholar
  51. 51.
    Cox SN, Hay E, Bird AC. Treatment of chronic macular edema with acetazolamide. Arch Ophthalmol. 1988;106:1190–5.CrossRefPubMedGoogle Scholar
  52. 52.
    Fishman GA, Fishman M, Maggiano J. Macular lesions associated with retinitis pigmentosa. Arch Ophthalmol. 1977;95:798–803.CrossRefPubMedGoogle Scholar
  53. 53.
    Makiyama Y, Oishi A, Otani A, Ogino K, Nakagawa S, Kurimoto M, et al. Prevalence and spatial distribution of cystoid spaces in retinitis pigmentosa: investigation with spectral domain optical coherence tomography. Retina. 2014;34:981–8.CrossRefPubMedGoogle Scholar

Copyright information

© Japanese Ophthalmological Society 2015

Authors and Affiliations

  • Tomoko Hasegawa
    • 1
  • Hanako O. Ikeda
    • 1
    • 2
    Email author
  • Noriko Nakano
    • 1
  • Yuki Muraoka
    • 1
  • Tatsuaki Tsuruyama
    • 3
  • Keiko Okamoto-Furuta
    • 3
  • Haruyasu Kohda
    • 3
  • Nagahisa Yoshimura
    • 1
  1. 1.Department of Ophthalmology and Visual SciencesKyoto University Graduate School of MedicineSakyo-ku, KyotoJapan
  2. 2.Institute for Advancement of Clinical and Translational ScienceKyoto University HospitalKyotoJapan
  3. 3.Center for Anatomical StudiesKyoto University Graduate School of MedicineKyotoJapan

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