Advertisement

Use of Direct Current Electroretinography for Analysis of Retinal Pigment Epithelium Function in Mouse Models

  • Minzhong Yu
  • Neal S. Peachey
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1753)

Abstract

A monolayer of pigmented epithelial cells, the retinal pigment epithelium (RPE), supports photoreceptor function in many ways. Consistent with these roles, RPE dysfunction underlies a number of hereditary retinal disorders. To monitor RPE function in vivo models for these conditions, we adapted an electroretinographic (ERG) technique based on direct current amplification (DC-ERG). This chapter describes the main features of this approach and its application to mouse models involving the RPE.

Key words

Direct current electroretinography Retinal pigment epithelium C-wave Fast oscillation Light peak Off-response 

References

  1. 1.
    Strauss O (2005) The retinal pigment epithelium in visual function. Physiol Rev 85(3):845–881CrossRefPubMedGoogle Scholar
  2. 2.
    Kikawada N (1968) Variations in the corneo-retinal standing potential of the vertebrate eye during light and dark adaptations. Jpn J Physiol 18(6):687–702CrossRefPubMedGoogle Scholar
  3. 3.
    Peachey NS, Stanton JB, Marmorstein AD (2002) Noninvasive recording and response characteristics of the rat dc-electroretinogram. Vis Neurosci 19(6):693–701CrossRefPubMedGoogle Scholar
  4. 4.
    Wu J, Peachey NS, Marmorstein AD (2004) Light-evoked responses of the mouse retinal pigment epithelium. J Neurophysiol 91(3):1134–1142CrossRefPubMedGoogle Scholar
  5. 5.
    Robson JG, Frishman LJ (2014) The rod-driven a-wave of the dark-adapted mammalian electroretinogram. Prog Retin Eye Res 39:1–22CrossRefPubMedGoogle Scholar
  6. 6.
    Penn RD, Hagins WA (1969) Signal transmission along retinal rods and the origin of the electroretinographic a-wave. Nature 223(5202):201–204CrossRefPubMedGoogle Scholar
  7. 7.
    Hagins WA, Penn RD, Yoshikami S (1970) Dark current and photocurrent in retinal rods. Biophys J 10(5):380–412CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Robson JG, Frishman LJ (1995) Response linearity and kinetics of the cat retina: the bipolar cell component of the dark-adapted electroretinogram. Vis Neurosci 12(5):837–850CrossRefPubMedGoogle Scholar
  9. 9.
    Tian N, Slaughter MM (1995) Correlation of dynamic responses in the ON bipolar neuron and the b-wave of the electroretinogram. Vis Res 35(10):1359–1364CrossRefPubMedGoogle Scholar
  10. 10.
    Robson JG, Frishman LJ (1996) Photoreceptor and bipolar cell contributions to the cat electroretinogram: a kinetic model for the early part of the flash response. J Opt Soc Am A Opt Image Sci Vis 13(3):613–622CrossRefPubMedGoogle Scholar
  11. 11.
    Robson JG, Maeda H, Saszik SM, Frishman LJ (2004) In vivo studies of signaling in rod pathways of the mouse using the electroretinogram. Vis Res 44(28):3253–3268CrossRefPubMedGoogle Scholar
  12. 12.
    Akopian A, Witkovsky P (2002) Calcium and retinal function. Mol Neurobiol 25(2):113–132CrossRefPubMedGoogle Scholar
  13. 13.
    Kofuji P, Ceelen P, Zahs KR, Surbeck LW, Lester HA, Newman EA (2000) Genetic inactivation of an inwardly rectifying potassium channel (Kir4.1 subunit) in mice: phenotypic impact in retina. J Neurosci 20(15):5733–5740PubMedPubMedCentralGoogle Scholar
  14. 14.
    Krapivinsky G, Medina I, Eng L, Krapivinsky L, Yang Y, Clapham DE (1998) A novel inward rectifier K+ channel with unique pore properties. Neuron 20(5):995–1005CrossRefPubMedGoogle Scholar
  15. 15.
    Shimura M, Yuan Y, Chang JT, Zhang S, Campochiaro PA, Zack DJ, Hughes BA (2001) Expression and permeation properties of the K(+) channel Kir7.1 in the retinal pigment epithelium. J Physiol 531(Pt 2):329–346CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Yuan Y, Shimura M, Hughes BA (2003) Regulation of inwardly rectifying K+ channels in retinal pigment epithelial cells by intracellular pH. J Physiol 549(Pt 2):429–438CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Yang D, Pan A, Swaminathan A, Kumar G, Hughes BA (2003) Expression and localization of the inwardly rectifying potassium channel Kir7.1 in native bovine retinal pigment epithelium. Invest Ophthalmol Vis Sci 44(7):3178–3185CrossRefPubMedGoogle Scholar
  18. 18.
    Yang D, Swaminathan A, Zhang X, Hughes BA (2008) Expression of Kir7.1 and a novel Kir7.1 splice variant in native human retinal pigment epithelium. Exp Eye Res 86(1):81–91CrossRefPubMedGoogle Scholar
  19. 19.
    Hughes BA, Swaminathan A (2008) Modulation of the Kir7.1 potassium channel by extracellular and intracellular pH. Am J Physiol Cell Physiol 294(2):C423–C431CrossRefPubMedGoogle Scholar
  20. 20.
    Pattnaik BR, Hughes BA (2009) Regulation of Kir channels in bovine retinal pigment epithelial cells by phosphatidylinositol 4,5-bisphosphate. Am J Physiol Cell Physiol 297(4):C1001–C1011CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Zhang W, Zhang X, Wang H, Sharma AK, Edwards AO, Hughes BA (2013) Characterization of the R162W Kir7.1 mutation associated with snowflake vitreoretinopathy. Am J Physiol Cell Physiol 304(5):C440–C449CrossRefPubMedGoogle Scholar
  22. 22.
    Wu J, Marmorstein AD, Kofuji P, Peachey NS (2004) Contribution of Kir4.1 to the mouse electroretinogram. Mol Vis 10:650–654PubMedPubMedCentralGoogle Scholar
  23. 23.
    Yu M, Zou W, Peachey NS, McIntyre TM, Liu J (2012) A novel role of complement in retinal degeneration. Invest Ophthalmol Vis Sci 53(12):7684–7692CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Möller A, Eysteinsson T, Steingrı́msson E (2004) Electroretinographic assessment of retinal function in microphthalmia mutant mice. Exp Eye Res 78(4):837–848Google Scholar
  25. 25.
    Linsenmeier RA, Steinberg RH (1984) Delayed basal hyperpolarization of cat retinal pigment epithelium and its relation to the fast oscillation of the DC electroretinogram. J Gen Physiol 83(2):213–232CrossRefPubMedGoogle Scholar
  26. 26.
    Griff ER, Steinberg RH (1984) Changes in apical [K+] produce delayed basal membrane responses of the retinal pigment epithelium in the gecko. J Gen Physiol 83(2):193–211CrossRefPubMedGoogle Scholar
  27. 27.
    Steinberg RH (1985) Interactions between the retinal pigment epithelium and the neural retina. Doc Ophthalmol 60(4):327–346CrossRefPubMedGoogle Scholar
  28. 28.
    Gallemore RP, Steinberg RH (1989) Effects of DIDS on the chick retinal pigment epithelium. II Mechanism of the light peak and other responses originating at the basal membrane. J Neurosci 9(6):1977–1984PubMedGoogle Scholar
  29. 29.
    Gallemore RP, Steinberg RH (1993) Light-evoked modulation of basolateral membrane cl- conductance in chick retinal pigment epithelium: the light peak and fast oscillation. J Neurophysiol 70(4):1669–1680CrossRefPubMedGoogle Scholar
  30. 30.
    Linsenmeier RA, Steinberg RH (1982) Origin and sensitivity of the light peak in the intact cat eye. J Physiol 331:653–673CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Gallemore RP, Griff ER, Steinberg RH (1988) Evidence in support of a photoreceptoral origin for the "light-peak substance". Invest Ophthalmol Vis Sci 29(4):566–571PubMedGoogle Scholar
  32. 32.
    Peterson WM, Meggyesy C, Yu K, Miller SS (1997) Extracellular ATP activates calcium signaling, ion, and fluid transport in retinal pigment epithelium. J Neurosci 17(7):2324–2337PubMedGoogle Scholar
  33. 33.
    Marmorstein LY, Wu J, McLaughlin P, Yocom J, Karl MO, Neussert R, Wimmers S, Stanton JB, Gregg RG, Strauss O, Peachey NS, Marmorstein AD (2006) The light peak of the electroretinogram is dependent on voltage-gated calcium channels and antagonized by bestrophin (best-1). J Gen Physiol 127(5):577–589CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Wu J, Marmorstein AD, Striessnig J, Peachey NS (2007) Voltage-dependent calcium channel CaV1.3 subunits regulate the light peak of the electroretinogram. J Neurophysiol 97(5):3731–3735CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Deutman AF (1969) Electro-oculography in families with vitelliform dystrophy of the fovea. Detection of the carrier state. Arch Ophthalmol 81(3):305–316CrossRefPubMedGoogle Scholar
  36. 36.
    Cross HE, Bard L (1974) Electro-oculography in Best's macular dystrophy. Am J Ophthalmol 77(1):46–50CrossRefPubMedGoogle Scholar
  37. 37.
    Zhang Y, Stanton JB, Wu J, Yu K, Hartzell HC, Peachey NS, Marmorstein LY, Marmorstein AD (2010) Suppression of Ca2+ signaling in a mouse model of best disease. Hum Mol Genet 19(6):1108–1118CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Edwards MM, Marin de Evsikova C, Collin GB, Gifford E, Wu J, Hicks WL, Whiting C, Varvel NH, Maphis N, Lamb BT, Naggert JK, Nishina PM, Peachey NS (2010) Photoreceptor degeneration, azoospermia, leukoencephalopathy, and abnormal RPE cell function in mice expressing an early stop mutation in CLCN2. Invest Ophthalmol Vis Sci 51(6):3264–3272CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Ganguly P, Alam SF (2015) Role of homocysteine in the development of cardiovascular disease. Nutr J 14(6)Google Scholar
  40. 40.
    Diaz-Arrastia R (2000) Homocysteine and neurologic disease. Arch Neurol 57(10):1422–1427CrossRefPubMedGoogle Scholar
  41. 41.
    Yu M, Sturgill-Short G, Ganapathy P, Tawfik A, Peachey NS, Smith SB (2012) Age-related changes in visual function in cystathionine-beta-synthase mutant mice, a model of hyperhomocysteinemia. Exp Eye Res 96(1):124–131CrossRefPubMedGoogle Scholar
  42. 42.
    Samuels IS, Bell BA, Pereira A, Saxon J, Peachey NS (2015) Early retinal pigment epithelium dysfunction is concomitant with hyperglycemia in mouse models of type 1 and type 2 diabetes. J Neurophysiol 113(4):1085–1099CrossRefPubMedGoogle Scholar
  43. 43.
    Tarchick MJ, Bassiri P, Rohwer RM, Samuels IS (2016) Early functional and morphologic abnormalities in the diabetic Nyxnob mouse retina. Invest Ophthalmol Vis Sci 57(7):3496–3508CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Bearse MA Jr, Ozawa GY (2014) Multifocal electroretinography in diabetic retinopathy and diabetic macular edema. Curr Diab Rep 14(9):526CrossRefPubMedGoogle Scholar
  45. 45.
    Samuels IS, Bell BA, Sturgill-Short G, Ebke LA, Rayborn M, Shi L, Nishina PM, Peachey NS (2013) Myosin 6 is required for iris development and normal function of the outer retina. Invest Ophthalmol Vis Sci 54(12):7223–7233CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Collin GB, Hubmacher D, Charette JR, Hicks WL, Stone L, Yu M, Naggert JK, Krebs MP, Peachey NS, Apte SS, Nishina PM (2015) Disruption of murine Adamtsl4 results in zonular fiber detachment from the lens and in retinal pigment epithelium dedifferentiation. Hum Mol Genet 24(24):6958–6974PubMedPubMedCentralGoogle Scholar
  47. 47.
    Saksens NT, Krebs MP, Schoenmaker-Koller FE, Hicks W, Yu M, Shi L, Rowe L, Collin GB, Charette JR, Letteboer SJ, Neveling K, van Moorsel TW, Abu-Ltaif S, De Baere E, Walraedt S, Banfi S, Simonelli F, Cremers FP, Boon CJ, Roepman R, Leroy BP, Peachey NS, Hoyng CB, Nishina PM, den Hollander AI (2016) Mutations in CTNNA1 cause butterfly-shaped pigment dystrophy and perturbed retinal pigment epithelium integrity. Nat Genet 48(2):144–151CrossRefPubMedGoogle Scholar
  48. 48.
    Patil H, Saha A, Senda E, Cho KI, Haque M, Yu M, Qiu S, Yoon D, Hao Y, Peachey NS, Ferreira PA (2014) Selective impairment of a subset of ran-GTP-binding domains of ran-binding protein 2 (Ranbp2) suffices to recapitulate the degeneration of the retinal pigment epithelium (RPE) triggered by Ranbp2 ablation. J Biol Chem 289(43):29767–29789CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Ridder W 3rd, Nusinowitz S, Heckenlively JR (2002) Causes of cataract development in anesthetized mice. Exp Eye Res 75(3):365–370CrossRefPubMedGoogle Scholar
  50. 50.
    Samuels IS, Sturgill GM, Grossman GH, Rayborn ME, Hollyfield JG, Peachey NS (2010) Light-Evoked Responses of the Retinal Pigment Epithelium: Changes Accompanying Photoreceptor Loss in the Mouse. J Neurophysiol 104(1):391–402Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Ophthalmic Research, Cole Eye InstituteCleveland Clinic FoundationClevelandUSA
  2. 2.Department of OphthalmologyCleveland Clinic Lerner College of Medicine of Case Western Reserve UniversityClevelandUSA
  3. 3.Louis Stokes Cleveland VA Medical CenterClevelandUSA

Personalised recommendations