Documenta Ophthalmologica

, Volume 128, Issue 2, pp 77–89 | Cite as

Mouse b-wave mutants

  • Machelle T. Pardue
  • Neal S. Peachey
Review Article


The b-wave is a major component of the electroretinogram that reflects the activity of depolarizing bipolar cells (DBCs). The b-wave is used diagnostically to identify patients with defects in DBC signaling or in transmission from photoreceptors to DBCs. In mouse models, an abnormal b-wave has been used to demonstrate a critical role of a particular protein in the release of glutamate from photoreceptor terminals, in establishing the structure of the photoreceptor-to-DBC synapse, in DBC signal transduction, and also in DBC development, survival, or metabolic support. The purpose of this review is to summarize these models and how they have advanced our understanding of outer retinal function.


Electroretinogram Retina b-Wave Depolarizing bipolar cell 



Work in the author’s laboratories has been supported by grants from the Department of Veterans Affairs, National Institutes of Health, a Foundation Fighting Blindness Center Grant to the Cole Eye Institute, and unrestricted grants from Research to Prevent Blindness to the Departments of Ophthalmology of Emory University and the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.


  1. 1.
    Heckenlively JR, Arden GB (2006) Principles and practice of clinical electrophysiology of vision, 2nd edn. MIT Press, CambridgeGoogle Scholar
  2. 2.
    Penn RD, Hagins WA (1969) Signal transmission along retinal rods and the origin of the electroretinographic a-wave. Nature 223:201–204PubMedGoogle Scholar
  3. 3.
    Newman EA (1985) Regulation of extracellular potassium by glial cells in the retina. Trends Neurosci 8:156–159Google Scholar
  4. 4.
    Newman EA, Odette LL (1984) Model of electroretinogram b-wave generation: a test of the K+ hypothesis. J Neurophysiol 51:164–182PubMedGoogle Scholar
  5. 5.
    Frishman LJ (2006) Origins of the electroretinogram. In: Heckenlively JR, Arden GB (eds) Principles and practice of clinical electrophysiology of vision, 2nd edn. MIT Press, Cambridge, pp 139–183Google Scholar
  6. 6.
    Karwoski CJ, Xu X (1999) Current-source density analysis of light-evoked field potentials in rabbit retina. Vis Neurosci 16:369–377PubMedGoogle Scholar
  7. 7.
    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 20:5733–5740PubMedCentralPubMedGoogle Scholar
  8. 8.
    Frishman LJ, Steinberg RH (1989) Light-evoked increases in [K+]o in proximal portion of the dark-adapted cat retina. J Neurophysiol 61:1233–1243PubMedGoogle Scholar
  9. 9.
    Green DG, Kapousta-Bruneau KV (1999) A dissection of the electroretinogram from the isolated rat retina with microelectrodes and drugs. Vis Neurosci 16:727–741PubMedGoogle Scholar
  10. 10.
    Lei B, Perlman I (1999) The contributions of voltage- and time-dependent potassium conductances to the electroretinogram in rabbits. Vis Neurosci 16:743–754PubMedGoogle Scholar
  11. 11.
    Bush RA, Sieving PA (1996) Inner retinal contributions to the primate photopic flash flicker electroretinogram. J Opt Soc Am A 13:557–565Google Scholar
  12. 12.
    Robson JG, Frishman LJ (1995) Response linearity and kinetics of the cat retina: the bipolar cell component of the dark-adapted electroretinogram. Vis Neurosci 12:837–850PubMedGoogle Scholar
  13. 13.
    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 13:613–622Google Scholar
  14. 14.
    Hood DC, Birch DG (1996) b Wave of the scotopic (rod) electroretinogram as a measure of the activity of human on-bipolar cells. J Opt Soc Am A 13:623–633Google Scholar
  15. 15.
    Sharma S, Ball S, Peachey NS (2005) Pharmacological studies of the mouse cone electroretinogram. Vis Neurosci 22:631–636PubMedGoogle Scholar
  16. 16.
    Sieving PA, Murayama K, Naarendorp F (1994) Push-pull model of the primate photopic electroretinogram: a role for hyperpolarizing bipolar neurons in shaping the b-wave. Vis Neurosci 11:519–532PubMedGoogle Scholar
  17. 17.
    McCall MM, Gregg RG (2008) Comparisons of structural and functional abnormalities in mouse b-wave mutants. J Physiol 586:4385–4392PubMedCentralPubMedGoogle Scholar
  18. 18.
    Pepperberg DR, Birch DG, Hood DC (1997) Photoresponses of human rods in vivo derived from paired-flash electroretinograms. Vis Neurosci 14:73–82PubMedGoogle Scholar
  19. 19.
    Kang Derwent JJ, Qtaishat NM, Pepperberg DR (2002) Excitation and desensitization of mouse rod photoreceptors in vivo following bright adapting light. J Physiol 541:201–218PubMedCentralPubMedGoogle Scholar
  20. 20.
    Kang Derwent JJ, Saszik SM, Maeda H, Little DM, Pardue MT, Frishman LJ, Pepperberg DR (2007) Test of the paired-flash electroretinographic method in mice lacking b-waves. Vis Neurosci 24:141–149PubMedGoogle Scholar
  21. 21.
    Peachey NS, Goto Y, Al-Ubaidi MR, Naash MI (1993) Properties of the mouse cone-mediated electroretinogram during light adaptation. Neurosci Lett 162:9–11PubMedGoogle Scholar
  22. 22.
    Lyubarsky AL, Falsini B, Pennesi ME, Valentini P, Pugh EN Jr (1999) UV- and midwave-sensitive cone-driven retinal responses of the mouse: a possible phenotype for coexpression of cone photopigments. J Neurosci 19:442–455PubMedGoogle Scholar
  23. 23.
    Xu X, Quiambao AB, Roveri L, Pardue MT, Marx JL, Röhlich P, Peachey NS, Al-Ubaidi MR (2000) Degeneration of cone photoreceptors induced by expression of the Mas1 oncogene. Exp Neurol 163:207–219PubMedGoogle Scholar
  24. 24.
    Morgans CW, Zhang J, Jeffrey BG, Nelson SM, Burke NS, Duvoisin RM, Brown RL (2009) TRPM1 is required for the depolarizing light response in retinal ON-bipolar cells. Proc Natl Acad Sci USA 106:19174–19178PubMedCentralPubMedGoogle Scholar
  25. 25.
    Shen Y, Heimel JA, Kammermans M, Peachey NS, Gregg RG, Nawy S (2009) A transient receptor potential-like channel mediates synaptic transmission in rod bipolar cells. J Neurosci 29:6088–6093PubMedCentralPubMedGoogle Scholar
  26. 26.
    Koike C, Obara T, Uriu Y, Numata T, Sanuki R, Miyata K, Koyasu T, Ueno S, Funabiki K, Tani A, Ueda H, Kondo M, Mori Y, Tachibana M, Furukawa T (2010) TRPM1 is a component of the retinal ON bipolar cell transduction channel in the mGluR6 cascade. Proc Natl Acad Sci USA 107:332–337PubMedCentralPubMedGoogle Scholar
  27. 27.
    Witkovsky P, Dudek FE, Ripps H (1975) Slow PIII component of the carp electroretinogram. J Gen Physiol 65:119–134PubMedGoogle Scholar
  28. 28.
    Wu J, Marmorstein AD, Kofuji P, Peachey NS (2004) Contribution of Kir4.1 to the mouse electroretinogram. Mol Vis 10:650–654PubMedCentralPubMedGoogle Scholar
  29. 29.
    Steinberg RH, Miller S (1973) Aspects of electrolyte transport in frog pigment epithelium. Exp Eye Res 16:365–372PubMedGoogle Scholar
  30. 30.
    Oakley B II, Green DG (1976) Correlation of light-induced changes in retinal extracellular potassium concentration with c-wave of the electroretinogram. J Neurophysiol 39:1117–1133PubMedGoogle Scholar
  31. 31.
    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 104:391–402PubMedCentralPubMedGoogle Scholar
  32. 32.
    Peachey NS, Sturgill-Short GM (2012) Response properties of slow PIII in the Large vls mutant. Doc Ophthalmol 125:203–209Google Scholar
  33. 33.
    Masu M, Iwakabe H, Tagawa Y, Miyoshi T, Yamashita M, Fukuda Y, Sasaki H, Hiroi K, Nakamura Y, Shigemoto R, Takada M, Nakamura K, Nakao K, Katsuki M, Nakanishi S (1995) Specific deficit of the ON response in visual transmission by targeted disruption of the mGIuR6 gene. Cell 80:757–765PubMedGoogle Scholar
  34. 34.
    Pinto LH, Vitaterna MH, Shimomura K, Siepka SM, Balannik V, McDearmon EL, Omura C, Lumayag S, Invergo BM, Glawe B, Cantrell DR, Inayat S, Olvera MA, Vessey KA, McCall MA, Maddox D, Morgans CW, Young B, Pletcher MT, Mullins RF, Troy JB, Takahashi JS (2007) Generation, identification and functional characterization of the nob4 mutation of Grm6 in the mouse. Vis Neurosci 24:111–123PubMedCentralPubMedGoogle Scholar
  35. 35.
    Maddox DM, Vessey KA, Yarbrough GL, Invergo BM, Cantrell DR, Inayat S, Balannik V, Hicks WL, Hawes NL, Byers S, Smith RS, Hurd R, Howell D, Gregg RG, Chang B, Naggert JK, Troy JB, Pinto LH, Nishina PM, McCall MA (2008) Allelic variance between GRM6 mutants, Grm6 nob3 and Grm6 nob4 results in differences in retinal ganglion cell visual responses. J Physiol 586:4409–4424PubMedCentralPubMedGoogle Scholar
  36. 36.
    Peachey NS, Pearring JN, Bojang P Jr, Hirschtritt ME, Sturgill-Short G, Ray TA, Furukawa T, Koike C, Goldberg AF, Shen Y, McCall MA, Nawy S, Nishina PM, Gregg RG (2012) Depolarizing bipolar cell dysfunction due to a Trpm1 point mutation. J Neurophysiol 108:2442–2451PubMedCentralPubMedGoogle Scholar
  37. 37.
    Pardue MT, McCall MA, LaVail MM, Gregg RG, Peachey NS (1998) A naturally-occurring mouse model of X-linked congenital stationary night blindness. Invest Ophthalmol Vis Sci 39:2443–2449PubMedGoogle Scholar
  38. 38.
    Gregg RG, Kamermans M, Klooster J, Lukasiewicz PD, Peachey NS, Vessey KA, McCall MA (2007) Nyctalopin expression in retinal bipolar cells restores visual function in a mouse model of complete X-linked congenital stationary night blindness. J Neurophysiol 98:3023–3033PubMedCentralPubMedGoogle Scholar
  39. 39.
    Pearring JN, Bojang P Jr, Shen Y, Koike C, Furukawa T, Nawy S, Gregg RG (2011) A role for nyctalopin, a small leucine rich repeat protein, in localizing the TRPM1 channel to retinal depolarizing bipolar cell dendrites. J Neurosci 31:10060–10066PubMedCentralPubMedGoogle Scholar
  40. 40.
    Peachey NS, Ray TA, Florijn R, Rowe LB, Sjoerdsma T, Contreras-Alcantara S, Baba K, Tosini G, Pozdeyev N, Iuvone PM, Bojang P Jr, Pearring JN, Simonsz HJ, van Genderen M, Birch DG, Traboulsi EI, Dorfman A, Lopez I, Ren H, Goldberg AFX, Nishina PM, Lachapelle P, McCall MA, Koenekoop RK, Bergen AAB, Kamermans M, Gregg RG (2012) GPR179 is required for depolarizing bipolar cell function and is mutated in autosomal-recessive complete congenital stationary night blindness. Am J Hum Genet 90:331–339PubMedCentralPubMedGoogle Scholar
  41. 41.
    Orlandi C, Posokhova E, Masuho I, Ray TA, Hasan N, Gregg RG, Martemyanov KA (2012) GPR158/179 regulate G protein signaling by controlling localization and activity of the RGS7 complexes. J Cell Biol 197:711–719PubMedCentralPubMedGoogle Scholar
  42. 42.
    Dhingra A, Lyubarsky A, Jiang M, Pugh EN Jr, Birnbaumer L, Sterling P, Vardi N (2000) The light response of ON bipolar neurons requires Gα0. J Neurosci 20:9053–9058PubMedGoogle Scholar
  43. 43.
    Dhingra A, Jiang M, Wang TL, Lyubarsky A, Savchenko A, Bar-Yehuda T, Sterling P, Birnbaumer L, Vardi N (2002) Light response of retinal ON bipolar cells requires a specific splice variant of Gα0. J Neurosci 22:4878–4884PubMedGoogle Scholar
  44. 44.
    Rao A, Dallman R, Henderson S, Chen CK (2007) Gbeta5 is required for normal light responses and morphology of retinal ON-bipolar cells. J Neurosci 27:14199–14204PubMedGoogle Scholar
  45. 45.
    Dhingra A, Ramakrishnan H, Neinstein A, Fina ME, Xu Y, Li J, Chung DC, Lyubarsky A, Vardi N (2012) Gβ3 is required for normal light ON responses and synaptic maintenance. J Neurosci 32:11343–11355PubMedCentralPubMedGoogle Scholar
  46. 46.
    Koike C, Numata T, Ueda H, Mori Y, Furukawa T (2010) TRPM1: a vertebrate TRP channel responsible for retinal ON bipolar function. Cell Calcium 48:95–101PubMedGoogle Scholar
  47. 47.
    Morgans CW, Brown RL, Duvoisin RM (2010) TRPM1: the endpoint of the mGluR6 signal transduction cascade in retinal ON-bipolar cells. BioEssays 32:609–614PubMedGoogle Scholar
  48. 48.
    Xu Y, Dhingra A, Fina ME, Koike C, Furukawa T, Vardi N (2012) mGluR6 deletion renders the TRPM1 channel in retina inactive. J Neurophysiol 107:948–957PubMedCentralPubMedGoogle Scholar
  49. 49.
    Rozzo A, Armellin M, Franzot J, Chiaruttini C, Nistri A, Tongiorgi E (2002) Expression and dendritic mRNA localization of GABAC receptor rho1 and rho2 subunits in developing rat brain and spinal cord. Eur J Neurosci 15:1747–1758PubMedGoogle Scholar
  50. 50.
    Cao Y, Masuho I, Okawa H, Xie K, Asami J, Kammermeier PJ, Maddox DM, Furukawa T, Inoue T, Sampath AP, Martemyanov KA (2009) Retina-specific GTPase accelerator RGS11/G beta 5S/R9AP is a constitutive heterotrimer selectively targeted to mGluR6 in ON-bipolar neurons. J Neurosci 29:9301–9313PubMedCentralPubMedGoogle Scholar
  51. 51.
    Cao Y, Pahlberg J, Sarria I, Kamasawa N, Sampath AP, Martemyanov KA (2012) Regulators of G protein signaling RGS7 and RGS11 determine the onset of the light response in ON bipolar neurons. Proc Natl Acad Sci USA 109:7905–7910PubMedCentralPubMedGoogle Scholar
  52. 52.
    Chen FS, Shim H, Morhardt D, Dallman R, Krahn E, McWhinney L, Rao A, Gold SJ, Chen CK (2010) Functional redundancy of R7 RGS proteins in ON-bipolar cell dendrites. Invest Ophthalmol Vis Sci 51:686–693PubMedCentralPubMedGoogle Scholar
  53. 53.
    Mojumder DK, Qian Y, Wensel TG (2009) Two R7 regulator of G-protein signaling proteins shape retinal bipolar cell signaling. J Neurosci 29:7753–7765PubMedCentralPubMedGoogle Scholar
  54. 54.
    Morgans CW, Liu W, Wensel TG, Brown RL, Perez-Leon JA, Bearnot B, Duvoisin RM (2007) Gβ5-RGS complexes co-localize with mGluR6 in retinal ON-bipolar cells. Eur J Neurosci 26:2899–2905PubMedCentralPubMedGoogle Scholar
  55. 55.
    Zhang J, Jeffrey BG, Morgans CW, Burke NS, Haley TL, Duvoisin RM, Brown RL (2010) RGS7 and -11 complexes accelerate the ON-bipolar cell light response. Invest Ophthalmol Vis Sci 51:1121–1129PubMedCentralPubMedGoogle Scholar
  56. 56.
    Shim H, Wang CT, Chen YL, Chau VQ, Fu KG, Yang J, McQuiston AR, Fisher RA, Chen CK (2012) Defective retinal depolarizing bipolar cells in regulators of G protein signaling (RGS) 7 and 11 double null mice. J Biol Chem 287:14873–14879PubMedCentralPubMedGoogle Scholar
  57. 57.
    Dryja TP, McGee TL, Berson EL, Fishman GA, Sandberg MA, Alexander KR, Derlacki DJ, Rajagopalan AS (2005) Night blindness and abnormal cone electroretinogram ON responses in patients with mutations in the GRM6 gene encoding mGluR6. Proc Natl Acad Sci USA 102:4884–4889PubMedCentralPubMedGoogle Scholar
  58. 58.
    Zeitz C, van Genderen M, Neidhardt J, Luhmann UF, Hoeben F, Forster U, Wycisk K, Mátyás G, Hoyng CB, Riemslag F, Meire F, Cremers FP, Berger W (2005) Mutations in GRM6 cause autosomal recessive congenital stationary night blindness with a distinctive scotopic 15-Hz flicker electroretinogram. Invest Ophthalmol Vis Sci 46:4328–4335PubMedGoogle Scholar
  59. 59.
    Bellone RR, Brooks SA, Sandmeyer L, Murphy BA, Forsyth G, Archer S, Bailey E, Grahn B (2008) Differential gene expression of TRPM1, the potential cause of congenital stationary night blindness and coat spotting patterns (LP) in the Appaloosa horse (Equus caballus). Genetics 179:1861–1870PubMedCentralPubMedGoogle Scholar
  60. 60.
    Audo I, Kohl S, Leroy BP, Munier FL, Guillonneau X, Mohand-Saïd S, Bujakowska K, Nandrot EF, Lorenz B, Preising M, Kellner U, Renner AB, Bernd A, Antonio A, Moskova-Doumanova V, Lancelot ME, Poloschek CM, Drumare I, Defoort-Dhellemmes S, Wissinger B, Léveillard T, Hamel CP, Schorderet DF, De Baere E, Berger W, Jacobson SG, Zrenner E, Sahel JA, Bhattacharya SS, Zeitz C (2009) TRPM1 is mutated in patients with autosomal-recessive complete congenital stationary night blindness. Am J Hum Genet 85:720–729PubMedCentralPubMedGoogle Scholar
  61. 61.
    Li Z, Sergouniotis PI, Michaelides M, Mackay DS, Wright GA, Devery S, Moore AT, Holder GE, Robson AG, Webster AR (2009) Recessive mutations of the gene TRPM1 abrogate ON bipolar cell function and cause complete congenital stationary night blindness in humans. Am J Hum Genet 85:711–719PubMedCentralPubMedGoogle Scholar
  62. 62.
    van Genderen MM, Bijveld MM, Claassen YB, Florijn RJ, Pearring JN, Meire FM, McCall MA, Riemslag FC, Gregg RG, Bergen AA, Kamermans M (2009) Mutations in TRPM1 are a common cause of complete congenital stationary night blindness. Am J Hum Genet 85:730–736PubMedCentralPubMedGoogle Scholar
  63. 63.
    Nakamura M, Sanuki R, Yasuma TR, Onishi A, Nishiguchi KM, Koike C, Kadowaki M, Kondo M, Miyake Y, Furukawa T (2010) TRPM1 mutations are associated with the complete form of congenital stationary night blindness. Mol Vis 16:425–437PubMedCentralPubMedGoogle Scholar
  64. 64.
    Bech-Hansen NT, Naylor MJ, Maybaum TA, Sparkes RL, Koop B, Birch DG, Bergen AA, Prinsen CF, Polomeno RC, Gal A, Drack AV, Musarella MA, Jacobson SG, Young RS, Weleber RG (2000) Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness. Nat Genet 26:319–323PubMedGoogle Scholar
  65. 65.
    Pusch CM, Zeitz C, Brandau O, Pesch K, Achatz H, Feil S, Scharfe C, Maurer J, Jacobi FK, Pinckers A, Andreasson S, Hardcastle A, Wissinger B, Berger W, Meindl A (2000) The complete form of X-linked congenital stationary night blindness is caused by mutations in a gene encoding a leucine-rich repeat protein. Nat Genet 26:324–327PubMedGoogle Scholar
  66. 66.
    Copenhagen DR, Jahr CE (1989) Release of endogenous excitatory amino acids from turtle photoreceptors. Nature 342:536–539Google Scholar
  67. 67.
    Marc RE, Liu W-LS, Kallionatis M, Raiguel SF, van Haesendonck E (1990) Patterns of glutamate immunoreactivity in the goldfish retina. J Neurosci 10:4006–4034PubMedGoogle Scholar
  68. 68.
    Zanazzi G, Matthews G (2009) The molecular architecture of ribbon presynaptic terminals. Mol Neurobiol 39:130–148PubMedCentralPubMedGoogle Scholar
  69. 69.
    Witkovsky P, Schmitz Y, Akopian A, Krizaj D, Tranchina D (1997) Gain of rod to horizontal cell synaptic transfer: relation to glutamate release and a dihydropyridine-sensitive calcium current. J Neurosci 17:7297–7306PubMedGoogle Scholar
  70. 70.
    Letts VA, Felix R, Biddlecome GH, Arikkath J, Mahaffey CL, Valenzuela A, Bartlett FS 2nd, Mori Y, Campbell KP, Frankel WN (1998) The mouse stargazer gene encodes a neuronal Ca2+-channel γ subunit. Nat Genet 19:340–347PubMedGoogle Scholar
  71. 71.
    Catterall WA (2000) Structure and regulation of voltage-gated Ca2+channels. Annu Rev Cell Dev Biol 16:521–555PubMedGoogle Scholar
  72. 72.
    Catterall WA, Dib-Hajj S, Meisler MH, Pietrobon D (2008) Inherited neuronal ion channelopathies: new windows on complex neurological diseases. J Neurosci 28:11768–11777PubMedCentralPubMedGoogle Scholar
  73. 73.
    Miyake Y, Yagasaki K, Horiguchi M, Kawase Y, Kanda T (1986) Congenital stationary night blindness with negative electroretinogram. A new classification. Arch Ophthalmol 104:1013–1020PubMedGoogle Scholar
  74. 74.
    Strom TM, Nyakatura G, Apfelstedt-Sylla E, Hellebrand H, Lorenz B, Weber BH, Wutz K, Gutwillinger N, Rüther K, Drescher B, Sauer C, Zrenner E, Meitinger T, Rosenthal A, Meindl A (1998) An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness. Nature Genet 19:260–263PubMedGoogle Scholar
  75. 75.
    Bech-Hansen NT, Naylor MJ, Maybaum TA, Pearce WG, Koop B, Fishman GA, Mets M, Musarella MA, Boycott KM (1998) Loss-of-function mutations in a calcium-channel alpha1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness. Nature Genet 19:264–267PubMedGoogle Scholar
  76. 76.
    Chang B, Heckenlively JR, Bayley PR, Brecha NC, Davisson MT, Hawes NL, Hirano AA, Hurd RE, Ikeda A, Johnson BA, McCall MA, Morgans CW, Nusinowitz S, Peachey NS, Rice DS, Vessey KA, Gregg RG (2006) The nob2 mouse, a null mutation in Cacna1f: anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses. Vis Neurosci 23:11–24PubMedCentralPubMedGoogle Scholar
  77. 77.
    Mansergh F, Orton NC, Vessey JP, Lalonde MR, Stell WK, Tremblay F, Barnes S, Rancourt DE, Bech-Hansen NT (2005) Mutation of the calcium channel gene Cacna1f disrupts calcium signaling, synaptic transmission and cellular organization in mouse retina. Hum Mol Genet 14:3035–3046PubMedGoogle Scholar
  78. 78.
    Ball SL, Powers PA, Shin HS, Morgans CW, Peachey NS, Gregg RG (2002) Role of the β2 subunit of voltage-dependent calcium channels in the retinal outer plexiform layer. Invest Ophthalmol Vis Sci 43:1595–1603PubMedGoogle Scholar
  79. 79.
    Ruether K, Grosse J, Matthiessen E, Hoffmann K, Hartmann C (2000) Abnormalities of the photoreceptor-bipolar cell synapse in a substrain of C57BL/10 mice. Invest Ophthalmol Vis Sci 41:4039–4047PubMedGoogle Scholar
  80. 80.
    Wycisk KA, Budde B, Feil S, Skosyrski S, Buzzi F, Neidhardt J, Glaus E, Nürnberg P, Ruether K, Berger W (2006) Structural and functional abnormalities of retinal ribbon synapses due to Cacna2d4 mutation. Invest Ophthalmol Vis Sci 47:3523–3530PubMedGoogle Scholar
  81. 81.
    Zeitz C, Labs S, Lorenz B, Forster U, Uksti J, Kroes HY, De Baere E, Leroy BP, Cremers FP, Wittmer M, van Genderen MM, Sahel JA, Audo I, Poloschek CM, Mohand-Saïd S, Fleischhauer JC, Hüffmeier U, Moskova-Doumanova V, Levin AV, Hamel CP, Leifert D, Munier FL, Schorderet DF, Zrenner E, Friedburg C, Wissinger B, Kohl S, Berger W (2009) Genotyping microarray for CSNB-associated genes. Invest Ophthalmol Vis Sci 50:5919–5926PubMedGoogle Scholar
  82. 82.
    Wycisk KA, Zeitz C, Feil S, Wittmer M, Forster U, Neidhardt J, Wissinger B, Zrenner E, Wilke R, Kohl S, Berger W (2006) Mutation in the auxiliary calcium-channel subunit CACNA2D4 causes autosomal recessive cone dystrophy. Am J Hum Genet 79:973–977PubMedCentralPubMedGoogle Scholar
  83. 83.
    Haeseleer F, Imanishi Y, Maeda T, Possin DE, Maeda A, Lee A, Rieke F, Palczewski K (2004) Essential role of Ca2+-binding protein 4, a Cav1.4 channel regulator, in photoreceptor synaptic function. Nature Neurosci 7:1079–1087PubMedCentralPubMedGoogle Scholar
  84. 84.
    Maeda T, Lem J, Palczewski K, Haeseleer F (2005) A critical role of CaBP4 in the cone synapse. Invest Ophthalmol Vis Sci 46:4320–4327PubMedCentralPubMedGoogle Scholar
  85. 85.
    Zeitz C, Kloeckener-Gruissem B, Forster U, Kohl S, Magyar I, Wissinger B, Mátyás G, Borruat FX, Schorderet DF, Zrenner E, Munier FL, Berger W (2006) Mutations in CABP4, the gene encoding the Ca2+-binding protein 4, cause autosomal recessive night blindness. Am J Hum Genet 79:657–667PubMedCentralPubMedGoogle Scholar
  86. 86.
    Littink KW, Koenekoop RK, van den Born LI, Collin RW, Moruz L, Veltman JA, Roosing S, Zonneveld MN, Omar A, Darvish M, Lopez I, Kroes HY, van Genderen MM, Hoyng CB, Rohrschneider K, van Schooneveld MJ, Cremers FP, den Hollander AI (2010) Homozygosity mapping in patients with cone-rod dystrophy: novel mutations and clinical characterizations. Invest Ophthalmol Vis Sci 51:5943–5951PubMedCentralPubMedGoogle Scholar
  87. 87.
    Littink KW, van Genderen MM, Collin RW, Roosing S, de Brouwer AP, Riemslag FC, Venselaar H, Thiadens AA, Hoyng CB, Rohrschneider K, den Hollander AI, Cremers FP, van den Born LI (2009) A novel homozygous nonsense mutation in CABP4 causes congenital cone-rod synaptic disorder. Invest Ophthalmol Vis Sci 50:2344–2350PubMedGoogle Scholar
  88. 88.
    Dick O, tom Dieck S, Altrock WD, Ammermuller J, Weiler R, Garner CC, Gundelfinger ED, Brandstatter JH (2003) The presynaptic active zone protein bassoon is essential for photoreceptor ribbon synapse formation in the retina. Neuron 37:775–786PubMedGoogle Scholar
  89. 89.
    Tom Dieck S, Specht D, Strenzke N, Hida Y, Krishnamoorthy V, Schmidt KF, Inoue E, Ishizaki H, Tanaka-Okamoto M, Miyoshi J, Hagiwara A, Brandstätter JH, Löwel S, Gollisch T, Ohtsuka T, Moser T (2012) Deletion of the presynaptic scaffold CAST reduces active zone size in rod photoreceptors and impairs visual processing. J Neurosci 32:12192–12203PubMedGoogle Scholar
  90. 90.
    Tom Dieck S, Specht D, Strenzke N, Hida Y, Krishnamoorthy V, Schmidt KF, Inoue E, Ishizaki H, Tanaka-Okamoto M, Miyoshi J, Hagiwara A, Brandstätter JH, Löwel S, Gollisch T, Ohtsuka T, Moser T (2010) Deletion of the presynaptic scaffold CAST reduces active zone size in rod photoreceptors and impairs visual processing. J Neurosci 32:12192–12203Google Scholar
  91. 91.
    Hirose T, Wolf E, Hara A (1977) Electrophysiological and psychophysical studies in congenital retinoschisis of X-linked recessive inheritance. Doc Ophthalmol Proc Ser 13:173–184Google Scholar
  92. 92.
    Peachey NS, Fishman GA, Derlacki DJ, Brigell MG (1987) Psychophysical and electroretinographic findings in X-linked juvenile retinoschisis. Arch Ophthalmol 105:513–516PubMedGoogle Scholar
  93. 93.
    Jablonski MM, Dalke C, Wang X, Lu L, Manly KF, Pretsch W, Favor J, Pardue MT, Rinchik EM, Williams RW, Goldowitz D, Graw J (2005) An ENU-induced mutation in Rs1h causes disruption of retinal structure and function. Mol Vis 11:569–581PubMedGoogle Scholar
  94. 94.
    Weber BH, Schrewe H, Molday LL, Gehrig A, White KL, Seeliger MW, Jaissle GB, Friedburg C, Tamm E, Molday RS (2002) Inactivation of the murine X-linked juvenile retinoschisis gene, Rs1h, suggests a role of retinoschisin in retinal cell layer organization and synaptic structure. Proc Natl Acad Sci USA 99:6222–6227PubMedCentralPubMedGoogle Scholar
  95. 95.
    Zeng Y, Takada Y, Kjellstrom S, Hiriyanna K, Tanikawa A, Wawrousek E, Smaoui N, Caruso R, Bush RA, Sieving PA (2004) RS-1 gene delivery to an adult Rs1h knockout mouse model restores ERG b-wave with reversal of the electronegative waveform of X-linked retinoschisis. Invest Ophthalmol Vis Sci 45:3279–3285PubMedGoogle Scholar
  96. 96.
    Takada Y, Vijayasarathy C, Zeng Y, Kjellstrom S, Bush RA, Sieving PA (2008) Synaptic pathology in retinoschisis knockout (Rs1 /y) mouse retina and modification by rAAV-Rs1 gene delivery. Invest Ophthalmol Vis Sci 49:3677–3686PubMedCentralPubMedGoogle Scholar
  97. 97.
    Park TK, Wu Z, Kjellstrom S, Zeng Y, Bush RA, Sieving PA, Colosi P (2009) Intravitreal delivery of AAV8 retinoschisin results in cell type-specific gene expression and retinal rescue in the Rs1-KO mouse. Gene Ther 16:916–926PubMedCentralPubMedGoogle Scholar
  98. 98.
    Shi L, Jian K, Ko ML, Trump D, Ko GY (2009) Retinoschisin, a new binding partner for L-type voltage-gated calcium channels in the retina. J Biol Chem 284:3966–3975PubMedCentralPubMedGoogle Scholar
  99. 99.
    Barresi R, Campbell KP (2006) Dystroglycan: from biosynthesis to pathogenesis of human disease. J Cell Sci 119:199–207PubMedGoogle Scholar
  100. 100.
    Montanaro F, Carbonetto S, Campbell KP, Lindenbaum M (1995) Dystroglycan expression in the wild type and mdx mouse neural retina: synaptic colocalization with dystrophin, dystrophin-related protein but not laminin. J Neurosci Res 42:528–538PubMedGoogle Scholar
  101. 101.
    Blank M, Koulen P, Blake DJ, Kröger S (1999) Dystrophin and beta-dystroglycan in photoreceptor terminals from normal and mdx3Cv mouse retinae. Eur J Neurosci 11:2121–2133PubMedGoogle Scholar
  102. 102.
    Jastrow H, Koulen P, Altrock WD, Kröger S (2006) Identification of a beta-dystroglycan immunoreactive subcompartment in photoreceptor terminals. Invest Ophthalmol Vis Sci 47:17–24PubMedGoogle Scholar
  103. 103.
    Omori Y, Araki F, Chaya T, Kajimura N, Irie S, Terada K, Muranishi Y, Tsujii T, Ueno S, Koyasu T, Tamaki Y, Kondo M, Amano S, Furukawa T (2012) Presynaptic dystroglycan-pikachurin complex regulates the proper synaptic connection between retinal photoreceptor and bipolar cells. J Neurosci 32:6126–6137PubMedGoogle Scholar
  104. 104.
    Lee Y, Kameya S, Cox GA, Hsu J, Hicks W, Maddatu TP, Smith RS, Naggert JK, Peachey NS, Nishina PM (2005) Ocular abnormalities in Large myd and Large vls mice, spontaneous models for muscle, eye and brain diseases. Mol Cell Neurosci 30:160–172PubMedGoogle Scholar
  105. 105.
    Holzfeind PJ, Grewal PK, Reitsamer HA, Kechvar J, Lassmann H, Hoeger H, Hewitt JE, Bittner RE (2002) Skeletal, cardiac and tongue muscle pathology, defective retinal transmission, and neuronal migration defects in the Large myd mouse defines a natural model for glycosylation-deficient muscle–eye–brain disorders. Hum Mol Genet 11:2673–2687PubMedGoogle Scholar
  106. 106.
    Cibis GW, Fitzgerald KM, Harris DJ, Rothberg PG, Rupani M (1993) The effects of dystrophin gene mutations on the ERG in mice and humans. Invest Ophthalmol Vis Sci 34:3646–3652PubMedGoogle Scholar
  107. 107.
    De Becker I, Riddell DC, Dooley JM, Tremblay F (1994) Correlation between electroretinogram findings and molecular analysis in the Duchenne muscular dystrophy phenotype. Br J Ophthalmol 78:719–722PubMedCentralPubMedGoogle Scholar
  108. 108.
    Fitzgerald KM, Cibis GW, Giambrone SA, Harris DJ (1994) Retinal signal transmission in Duchenne muscular dystrophy: evidence for dysfunction in the photoreceptor/depolarizing bipolar cell pathway. J Clin Invest 93:2425–2430PubMedCentralPubMedGoogle Scholar
  109. 109.
    Pillers DA, Bulman DE, Weleber RG, Sigesmund DA, Musarella MA, Powell BR, Murphey WH, Westall C, Panton C, Becker LE, Worton RG, Ray PN (1993) Dystrophin expression in the human retina is required for normal function as defined by electroretinography. Nat Genet 4:82–86PubMedGoogle Scholar
  110. 110.
    Sigesmund DA, Weleber RG, Pillers DA, Westall CA, Panton CM, Powell BR, Héon E, Murphey WH, Musarella MA, Ray PN (1994) Characterization of the ocular phenotype of Duchenne and Becker muscular dystrophy. Ophthalmology 101:856–865PubMedGoogle Scholar
  111. 111.
    Tremblay F, De Becker I, Riddell DC, Dooley JM (1994) Duchenne muscular dystrophy: negative scotopic bright-flash electroretinogram and normal dark adaptation. Can J Ophthalmol 29:280–283PubMedGoogle Scholar
  112. 112.
    Tremblay F, De Becker I, Dooley JM, Riddell DC (1994) Duchenne muscular dystrophy: negative scotopic bright-flash electroretinogram but not congenital stationary night blindness. Can J Ophthalmol 29:274–279PubMedGoogle Scholar
  113. 113.
    D’Souza VN, Nguyen TM, Morris GE, Karges W, Pillers DA, Ray PN (1995) A novel dystrophin isoform is required for normal retinal electrophysiology. Hum Mol Genet 4:837–842PubMedGoogle Scholar
  114. 114.
    Pillers DA, Weleber RG, Woodward WR, Green DG, Chapman VM, Ray PN (1995) mdxCv3 mouse is a model for electroretinography of Duchenne/Becker muscular dystrophy. Invest Ophthalmol Vis Sci 36:462–466PubMedGoogle Scholar
  115. 115.
    Pillers DA, Weleber RG, Green DG, Rash SM, Dally GY, Howard PL, Powers MR, Hood DC, Chapman VM, Ray PN, Woodward WR (1999) Effects of dystrophin isoforms on signal transduction through neural retina: genotype-phenotype analysis of Duchenne muscular dystrophy mouse mutants. Mol Genet Metab 66:100–110PubMedGoogle Scholar
  116. 116.
    Pillers DA, Fitzgerald KM, Duncan NM, Rash SM, White RA, Dwinnell SJ, Powell BR, Schnur RE, Ray PN, Cibis GW, Weleber RG (1999) Duchenne/Becker muscular dystrophy: correlation of phenotype by electroretinography with sites of dystrophin mutations. Hum Genet 105:2–9PubMedGoogle Scholar
  117. 117.
    Satz JS, Philp AR, Nguyen H, Kusano H, Lee J, Turk R, Riker MJ, Hernández J, Weiss RM, Anderson MG, Mullins RF, Moore SA, Stone EM, Campbell KP (2009) Visual impairment in the absence of dystroglycan. J Neurosci 29:13136–13146PubMedCentralPubMedGoogle Scholar
  118. 118.
    Libby RT, Lavallee CR, Balkema GW, Brunken WJ, Hunter DD (1999) Disruption of laminin beta2 chain production causes alterations in morphology and function in the CNS. J Neurosci 19:9399–9411PubMedGoogle Scholar
  119. 119.
    Kur J, Newman EA, Chan-Ling T (2012) Cellular and physiological mechanisms underlying blood flow regulation in the retina and choroid in health and disease. Prog Retin Eye Res 31:377–406PubMedCentralPubMedGoogle Scholar
  120. 120.
    Ye X, Wang Y, Nathans J (2010) The Norrin/Frizzled4 signaling pathway in retinal vascular development and disease. Trends Mol Med 16:417–425PubMedCentralPubMedGoogle Scholar
  121. 121.
    Berger W, van de Pol D, Bachner D, Oerlemans F, Winkens H, Hameister H, Wieringa B, Hendriks W, Ropers HH (1996) An animal model for Norrie disease (ND): gene targeting of the mouse ND gene. Hum Mol Genet 5:51–59PubMedGoogle Scholar
  122. 122.
    Ruether K, van de Pol D, Jaissle G, Berger W, Tornow RP, Zrenner E (1997) Retinoschisis like alterations in the mouse eye caused by gene targeting of the Norrie disease gene. Invest Ophthalmol Vis Sci 38:710–718PubMedGoogle Scholar
  123. 123.
    Ohlmann A, Scholz M, Goldwich A, Chauhan BK, Hudl K, Ohlmann AV, Zrenner E, Berger W, Cvekl A, Seeliger MW, Tamm ER (2005) Ectopic norrin induces growth of ocular capillaries and restores normal retinal angiogenesis in Norrie disease mutant mice. J Neurosci 25:1701–1710PubMedGoogle Scholar
  124. 124.
    Xu Q, Wang Y, Dabdoub A, Smallwood PM, Williams J, Woods C, Kelley MW, Jiang L, Tasman W, Zhang K, Nathans J (2004) Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell 116:883–895PubMedGoogle Scholar
  125. 125.
    Ye X, Wang Y, Cahill H, Yu M, Badea TC, Smallwood PM, Peachey NS, Nathans J (2009) Norrin, frizzled-4, and Lrp5 signaling in endothelial cells controls a genetic program for retinal vascularization. Cell 139:285–298PubMedCentralPubMedGoogle Scholar
  126. 126.
    Xia CH, Liu H, Cheung D, Wang M, Cheng C, Du X, Chang B, Beutler B, Gong X (2008) A model for familial exudative vitreoretinopathy caused by LPR5 mutations. Hum Mol Genet 17:1605–1612PubMedCentralPubMedGoogle Scholar
  127. 127.
    Xia CH, Yablonka-Reuveni Z, Gong X (2010) LRP5 is required for vascular development in deeper layers of the retina. PLoS One 5:e11676PubMedCentralPubMedGoogle Scholar
  128. 128.
    Haverkamp S, Wassle H (2000) Immunocytochemical analysis of the mouse retina. J Comp Neurol 424:1–23PubMedGoogle Scholar
  129. 129.
    Ruether K, Feigenspan A, Pirngruber J, Leitges M, Baehr W, Strauss O (2010) PKCα is essential for the proper activation and termination of rod bipolar cell response. Invest Ophthalmol Vis Sci 51:6051–6058PubMedCentralPubMedGoogle Scholar
  130. 130.
    Xiong W-H, Tekmen-Clark M, Lolich S, Duvoisin RM, Morgans CW (2013) The effect of PKCα on the electroretinogram. ARVO Abstr #6162Google Scholar
  131. 131.
    Peachey NS, Roveri L, Messing A, McCall MA (1997) Functional consequences of oncogene-induced horizontal cell degeneration in the retinas of transgenic mice. Vis Neurosci 14:627–632PubMedGoogle Scholar
  132. 132.
    Sonntag S, Dedek K, Dorgau B, Schultz K, Schmidt KF, Cimiotti K, Weiler R, Löwel S, Willecke K, Janssen-Bienhold U (2012) Ablation of retinal horizontal cells from adult mice leads to rod degeneration and remodeling in the outer retina. J Neurosci 32:10713–10724PubMedGoogle Scholar
  133. 133.
    Bramblett DE, Pennesi ME, Wu SM, Tsai M-J (2004) The transcription factor Blhlb4 is required for rod bipolar cell maturation. Neuron 43:779–793PubMedGoogle Scholar
  134. 134.
    Brzezinski JA, Brown NL, Tanikawa A, Bush RA, Sieving PA, Vitaterna MH, Takahashi JS, Glaser T (2005) Loss of circadian photoentrainment and abnormal retinal electrophysiology in Math5 mutant mice. Invest Ophthalmol Vis Sci 46:2540–2551PubMedCentralPubMedGoogle Scholar
  135. 135.
    Ohtoshi A, Wang SW, Maeda H, Saszik SM, Frishman LJ, Klein WH, Behringer RR (2004) Regulation of retinal cone bipolar cell differentiation and photopic vision by the CVC homeobox gene Vsx1. Curr Biol 14:530–536PubMedGoogle Scholar
  136. 136.
    Peachey NS, Quiambao AB, Xu X, Pardue MT, Roveri L, McCall MA, Al-Ubaidi MR (2003) Loss of bipolar cells resulting from the expression of bcl-2 directed by the IRBP promoter. Exp Eye Res 77:477–483PubMedGoogle Scholar
  137. 137.
    Zhu X, Wu K, Rife L, Cawley NX, Brown B, Adams T, Teofilo K, Lillo C, Williams DS, Loh P, Craft CM (2005) Carboxypeptidase E is required for normal synaptic transmission from photoreceptors to the inner retina. J Neurochem 95:1351–1362PubMedGoogle Scholar
  138. 138.
    Liu J, Ball SL, Yang Y, Mei P, Zhang L, Shi H, Kaminski HJ, Lemmon VP, Hu H (2006) A genetic model for muscle-eye-brain disease in mice lacking protein O-mannose beta1,2-N-acetylglucosaminyltransferase (POMGnT1). Mech Dev 123:228–240PubMedGoogle Scholar
  139. 139.
    Sato S, Omori Y, Katoh K, Kondo M, Kanagawa M, Miyata K, Funabiki K, Koyasu T, Kajimura N, Miyoshi T, Sawai H, Kobayashi K, Tani A, Toda T, Usukura J, Tano Y, Fujikado T, Furukawa T (2008) Pikachurin, a dystroglycan ligand, is essential for photoreceptor ribbon synapse formation. Nat Neurosci 11:923–931PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg (outside the USA) 2014

Authors and Affiliations

  1. 1.Rehabilitation Research and Development Center of ExcellenceAtlanta VA Medical CenterDecaturUSA
  2. 2.Department of OphthalmologyEmory University School of MedicineAtlantaUSA
  3. 3.Research Service (151W)Louis Stokes Cleveland VA Medical CenterClevelandUSA
  4. 4.Cole Eye InstituteCleveland ClinicClevelandUSA
  5. 5.Department of Ophthalmology, Cleveland Clinic Lerner College of MedicineCase Western Reserve UniversityClevelandUSA

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