Hostname: page-component-cd9895bd7-hc48f Total loading time: 0 Render date: 2024-12-25T02:26:22.443Z Has data issue: false hasContentIssue false
  • English
  • Français

Normal photoresponses and altered b-wave responses to APB in the mdxCv3 mouse isolated retina ERG supports role for dystrophin in synaptic transmission

Published online by Cambridge University Press:  01 September 2004

DANIEL G. GREEN ,
HAO GUO  and
DE-ANN M. PILLERS
DANIEL G. GREEN
Affiliation:
Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan
HAO GUO
Affiliation:
Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan Current address: CTO, Howell Co. Ltd, 6 Yongding Xili Road, Beijing, China
DE-ANN M. PILLERS
Affiliation:
Departments of Pediatrics, Ophthalmology and Molecular and Medical Genetics, Doernbecher Children's Hospital, Casey Eye Institute, Oregon Health & Science University, Portland, Oegon
Get access Rights & Permissions [Opens in a new window]

Abstract

The mdxCv3 mouse is a model for Duchenne muscular dystrophy (DMD). DMD is an X-linked disorder with defective expression of the protein dystrophin, and which is associated with a reduced b-wave and has other electro- retinogram (ERG) abnormalities. To assess potential causes for the abnormalities, we recorded ERGs from pieces of isolated C57BL/6J and mdxCv3 mouse retinas, including measurements of transretinal and intraretinal potentials. The ERGs from the isolated mdxCv3 retina differ from those of control retinas in that they show reduced b-wave amplitudes and increased b-wave implicit times. Photovoltages obtained by recording across the photoreceptor outer segments of the retinas did not differ from normal, suggesting that the likely causes of the reduced b-wave are localized to the photoreceptor to ON-bipolar synapse. At a concentration of 50 μM, the glutamate analog DL-2-amino-4-phosphonobutyric acid (APB) blocks the b-wave component of the ERG, by binding to sites on the postsynaptic membrane. The On-bipolar cell contribution to the ERG was inferred by extracting the component that was blocked by APB. We found that this component was smaller in amplitude and had longer response latencies in the mdxCv3 mice, but was of similar overall time course. To assess the sensitivity of sites on the postsynaptic membrane to glutamate, the concentration of APB in the media was systematically varied, and the magnitude of blockage of the light response was quantified. We found that the mdxCv3 retina was 5-fold more sensitive to APB than control retinas. The ability of lower concentrations of APB to block the b-wave in mdxCv3 suggests that the ERG abnormalities may reflect alterations in either glutamate release, the glutamate postsynaptic binding sites, or in other proteins that modulate glutamate function in ON-bipolar cells.

Keywords

Isolated mdxCv3 mouse retinaIntraretinal ERGNormal light transductionAbnormal depolarizing bipolar cell activityHigh sensitivity to APB
Type
Research Article
Information
Visual Neuroscience , Volume 21 , Issue 5 , September 2004 , pp. 739 - 747
Copyright
2004 Cambridge University Press

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

REFERENCES

Ahn, A.H. & Kunkel, L.M. (1993). The structural and functional diversity of dystrophin. Nature Genetics 3, 283–291.Google Scholar
Ashmore, J.F. & Falk, G. (1980). Responses of rod bipolar cells in the dark adapted retina of the dogfish, Scyliorhinus canicula. Journal of Physiology 300, 115–150.Google Scholar
Balkema, G.W., Pinto, L.H., Drager, U.C., & Vanable, J.W. (1981). Characterization of abnormalities in the visual system of the mutant mouse pearl. Journal of Neuroscience 1, 1320–1329.Google Scholar
Blank, M., Koulen, P., Blake, D.J., & Kroger, S. (1999). Dystrophin and beta-dystroglycan in photoreceptor terminals from normal and mdx3Cv mouse retinae. European Journal of Neuroscience 11, 2121–2133.Google Scholar
Bollmann, J.H., Sakmann, B., & Borst, J.G. (2000). Calcium sensitivity of glutamate release in a calyx-type terminal. Science 289, 953–957.Google Scholar
Cheng, Y. & Prusoff, W.H. (1973). Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochemical Pharmacology 22, 3099–3108.Google Scholar
Cibis, G.W., Fitzgerald, K.M., Harris, D.J., Rothberg, P.G., & Rupani, M. (1993). The effects of dystrophin gene mutations on the ERG in mice and humans. Investigative Ophthalmology and Visual Science 34, 3646–3652.Google Scholar
Claudepierre, T., Rodius, F., Frasson, M., Fontaine, V., Picaud, S., Dreyfus, H., Mornet, D., & Rendon, A. (1999). Differential distribution of dystrophins in rat retina. Investigative Ophthalmology and Visual Science 40, 1520–1529.Google Scholar
Cox, G.A., Phelps, S.F., Chapman, V.M., & Chamberlain, J.S. (1993). New mdx mutation disrupts expression of muscle and nonmuscle isoforms of dystrophin. Nature Genetics 4, 87–93.Google Scholar
Dalloz, C., Claudepierre, T., Rodius, F., Mornet, D., Sahel, J., & Rendon, A. (2001). Differential distribution of the members of the dystrophin glycoprotein complex in mouse retina: Effect of the mdx(3Cv) mutation. Molecular and Cellular Neuroscience 17, 908–920.Google Scholar
D'Souza, V.N., Nguyen, T.M., Morris, G.E., Karges, W., Pillers, D.M., & Ray, P.N. (1995). A novel dystrophin isoform is required for normal retinal electrophysiology. Human Molecular Genetics 4, 837–842.Google Scholar
Emery, A.E.H. (1993). Duchenne Muscular Dystrophy, 2nd edition. Oxford, UK: Oxford University Press.
Field, G.D. & Rieke, F. (2002). Nonlinear signal transfer from mouse rods to bipolar cells and implications for visual sensitivity. Neuron 34, 773–785.Google Scholar
Frishman, L.J., Yamamoto, F., Bogucka, J., & Steinberg, R.H. (1992). Light-evoked changes in [K+]o in proximal portion of light-adapted cat retina. Journal of Neurophysiology 67, 1201–1212.Google Scholar
Green, D.G. & Kapousta-Bruneau, N.V. (1999a). Electrophysiological properties of a new isolated retina preparation. Vision Research 39, 2165–2177.Google Scholar
Green, D.G. & Kapousta-Bruneau, N.V. (1999b). A dissection of the ERG from the isolated rat retina with microelectrodes and drugs. Visual Neuroscience 16, 727–741.Google Scholar
Gurevich, L. & Slaughter, M.M. (1993). Comparison of the waveforms of the ON bipolar neuron and the b-wave of the electroretinogram. Vision Research 33, 2431–2435.Google Scholar
Ino-Ue, M., Honda, S., Nishio, H., Matsuo, M., Nakamura, H., & Yamamoto, M. (1997). Genotype and electroretinal heterogeneity in Duchenne muscular dystrophy. Experimental Eye Research 65, 861–864.Google Scholar
Jamison, J.A., Bush, R.A., Lei, B., & Sieving, P.A. (2001). Characterization of the rod photoresponse isolated from the dark-adapted primate ERG. Visual Neuroscience 18, 445–455.Google Scholar
Kang Derwent, J.J. & Linsenmeier, R.A. (2001). Intraretinal analysis of the a-wave of the electroretinogram (ERG) in dark-adapted intact cat retina. Visual Neuroscience 18, 353–363.Google Scholar
Kim, H.G. & Miller, R.F. (1993). Properties of synaptic transmission from photoreceptors to bipolar cells in the mudpuppy retina. Journal of Neurophysiology 69, 352–360.Google Scholar
Knapp, A.G. & Schiller, P.H. (1984). The contribution of on-bipolar cells to the electroretinogram of rabbits and monkeys. A study using 2-amino-4-phosphonobutyrate (APB). Vision Research 24, 1841–1846.Google Scholar
McGillem, G.S. & Dacheux, R.F. (2001). Rabbit cone bipolar cells: Correlation of their morphologies with whole-cell recordings. Visual Neuroscience 18, 675–685.Google Scholar
Penn, R.D. & Hagins, W.A. (1972). Kinetics of the photocurrent of retinal rods. Biophysical Journal 12, 1073–1094.Google Scholar
Pillers, D.M., Bulman, D.E., Weleber, R.G., Sigesmund, D.A., Musarella, M.A., Powell, B.R., Murphey, W.H., Westall, C., Panton, C., & Becker, L.E. (1993). Dystrophin expression in the human retina is required for normal function as defined by electroretinography. Nature Genetics 4, 82–86.Google Scholar
Pillers, D.M., Fitzgerald, K.M., Duncan, N.M., Rash, S.M., White, R.A., Dwinnell, S.J., Powell, B.R., Schnur, R.E., Ray, P.N., Cibis, G.W., & Weleber, R.G. (1999a). Duchenne/Becker muscular dystrophy: Correlation of phenotype by electroretinography with sites of dystrophin mutations. Human Genetics 105, 2–9.Google Scholar
Pillers, D.M., Weleber, R.G., Green, D.G., Rash, S.M., Dally, G.Y., Howard, P.L., Powers, M.R., Hood, D.C., Chapman, V.M., Ray, P.N., & Woodward, W.R. (1999b). Effects of dystrophin isoforms on signal transduction through neural retina: Genotype-phenotype analysis of duchenne muscular dystrophy mouse mutants. Molecular Genetics and Metabolism 66, 100–110.Google Scholar
Pillers, D.M., Weleber, R.G., Powell, B.R., Hanna, C.E., Magenis, R.E., & Buist, N.R. (1990). Åland Island eye disease (Forsius-Eriksson ocular albinism) and an Xp21 deletion in a patient with Duchenne muscular dystrophy, glycerol kinase deficiency, and congenital adrenal hypoplasia. American Journal of Medical Genetics 36, 23–28.Google Scholar
Pillers, D.M., Weleber, R.G., Woodward, W.R., Green, D.G., Chapman, V.M., & Ray, P.N. (1995). mdxCv3 mouse is a model for electroretinography of Duchenne/Becker muscular dystrophy. Investigative Ophthalmology and Visual Science 36, 462–466.Google Scholar
Robson, J.G. & Frishman, L.J. (1995). Response linearity and kinetics of the cat retina: The bipolar cell component of the dark adapted electroretinogram. Visual Neuroscience 12, 837–850.Google Scholar
Robson, J.G. & Frishman, L.J. (1996). Photoreceptor and bipolar cell contributions to the cat electroretinogram: A kinetic model for the early part of the flash response. Journal of the Optical Society of America A—Optic and Image Science 13, 613–622.Google Scholar
Robson, J.G., Maeda, H., Saszik, S.M., & Frishman, L.J. (2004). In vivo studies of signaling in rod pathways of the mouse using the electroretinogram. Vision Research. In press.Google Scholar
Sabatini, B.L. & Regehr, W.G. (1999). Timing of synaptic transmission. Annual Review Physiology 61, 521–542.Google Scholar
Saszik, S.M., Robson, J.G., & Frishman, L.J. (2002). The scotopic threshold response of the dark-adapted electroretinogram of the mouse. Journal of Physiology 543, 899–916.Google Scholar
Shiells, R.A. & Falk, G. (1994). Responses of rod bipolar cells isolated from dogfish retinal slices to concentration-jumps of glutamate. Visual Neuroscience 11, 1175–1183.Google Scholar
Shiells, R.A. & Falk, G. (1999). Contribution of rod, on-bipolar, and horizontal cell light responses to the ERG of dogfish retina. Visual Neuroscience 16, 503–511.Google Scholar
Sieving, P.A., Fowler, M.L., Bush, R.A., Machida, S., Calvert, P.D., Green, D.G., Makino, C.L., & Mchenry, C.L. (2001). Constitutive “light” adaptation in rods from G90D rhodopsin: A mechanism for human congenital nightblindness without rod cell loss. Journal of Neuroscience 21, 5449–5460.Google Scholar
Stockton, R.A. & Slaughter, M.M. (1989). B-wave of the electroretinogram: A reflection of ON bipolar cell activity. Journal of General Physiology 93, 101–122.Google Scholar
Stone, C. & Pinto, L.H. (1993). Response properties of ganglion cells in the isolated mouse retina. Visual Neuroscience 10, 31–39.Google Scholar
Suzuki, H. & Pinto, L.H. (1986). Response properties of horizontal cells in the isolated retina of wild-type and pearl mutant mice. Journal of Neuroscience 6, 1122–1128.Google Scholar
Tian, N. & Slaughter, M.M. (1995). Correlation of dynamic responses in the ON bipolar neuron and the b-wave of electroretinogram. Vision Research 35, 1359–1364.Google Scholar
Tokarz, S.A., Duncan, N.M., Rash, S.M., Sadeghi, A., Dewan, A.K., & Pillers, D.M. (1998). Redefinition of dystrophin isoform distribution in mouse tissue by RT-PCR implies role in nonmuscle manifestations of Duchenne muscular dystrophy. Molecular Genetics and Metabolism 65, 272–281.Google Scholar