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Reduced synaptic vesicle density and aberrant synaptic localization caused by a splice site mutation in the Rs1h gene

Published online by Cambridge University Press:  30 January 2007

BRITT A. JOHNSON ,
SAKAE IKEDA ,
LAWRENCE H. PINTO  and
AKIHIRO IKEDA
BRITT A. JOHNSON
Affiliation:
Department of Medical Genetics, University of Wisconsin-Madison, Madison, Wisconsin
SAKAE IKEDA
Affiliation:
Department of Medical Genetics, University of Wisconsin-Madison, Madison, Wisconsin
LAWRENCE H. PINTO
Affiliation:
Department of Neurobiology & Physiology, Northwestern University, Evanston, Illinois
AKIHIRO IKEDA
Affiliation:
Department of Medical Genetics, University of Wisconsin-Madison, Madison, Wisconsin
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Abstract

X-linked retinoschisis (XLRS) is a common form of inherited macular degeneration caused by mutations in the RS1 gene. Whereas the role of RS1 has been implicated in the synaptic structure as well as layer organization in the retina, the pathological effect of a defective RS1 gene on the synaptic interaction between photoreceptor cells and second-order neurons has not been thoroughly investigated. In this study, we perform a detailed characterization of the retinal synaptic phenotypes caused by a splice site mutation in the murine RS1 homolog (Rs1htmgc1). Electron microscopic analysis showed that presynaptic terminals of photoreceptor cells contain a lower areal density of synaptic vesicles in the Rs1htmgc1 retina. Examination of the synaptic interactions in the outer plexiform layer also revealed ectopic localization of photoreceptor cell presynaptic markers and elongation of neurites from postsynaptic neurons (bipolar and horizontal cells), which are observed in other mouse models with defective photoreceptor cell molecules. Consistent with these synaptic abnormalities, ERG analysis of young Rs1htmgc1 mice revealed attenuation of the b-wave with preservation of the a-wave. These results demonstrate that RS1H has functional significance in the morphology and function of the synapse between photoreceptors and second-order neurons. A developmental study from postnatal day (P) 15 through P19 showed that synaptic interactions form normally, and structural abnormalities occur after completion of synaptic formation suggesting that RS1H is important for the maintenance of this synaptic interaction. Thus, Rs1htmgc1 mice may serve as a new genetic model for human XLRS and other synaptic disorders.

Keywords

RetinoschisinOuter plexiform layerSynaptic vesiclesERG b-wave lossSynaptic morphology
Type
Research Article
Information
Visual Neuroscience , Volume 23 , Issue 6 , November 2006 , pp. 887 - 898
Copyright
© 2006 Cambridge University Press

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References

REFERENCES

Bamji, S.X., Shimazu, K., Kimes, N., Huelsken, J., Birchmeier, W., Lu, B., & Reichardt, L.F. (2003). Role of beta-catenin in synaptic vesicle localization and presynaptic assembly. Neuron 40, 719–731.CrossRefGoogle Scholar
Baumgartner, S., Hofmann, K., Chiquet-Ehrismann, R., & Bucher, P. (1998). The discoidin domain family revisited: new members from prokaryotes and a homology-based fold prediction. Protein Science 7, 1626–1631.CrossRefGoogle Scholar
Bellocchio, E.E., Reimer, R.J., Fremeau, R.T., Jr., & Edwards, R.H. (2000). Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter. Science 289, 957–960.CrossRefGoogle Scholar
Blanks, J.C., Adinolfi, A.M., & Lolley, R.N. (1974). Synaptogenesis in the photoreceptor terminal of the mouse retina. Journal of Comparative Neurology 156, 81–93.CrossRefGoogle Scholar
Bradshaw, K., Newman, D., Allen, L., & Moore, A. (2003). Abnormalities of the scotopic threshold response correlated with gene mutation in X-linked retinoschisis and congenital stationary night blindness. Documenta Ophthalmologica 107, 155–164.CrossRefGoogle Scholar
Brose, N., Petrenko, A.G., Sudhof, T.C., & Jahn, R. (1992). Synaptotagmin: a calcium sensor on the synaptic vesicle surface. Science 256, 1021–1025.CrossRefGoogle Scholar
Chang, B., Heckenlively, J.R., Bayley, P.R., Brecha, N.C., Davisson, M.T., Hawes, N.L., Hirano, A.A., Hurd, R.E., Ikeda, A., Johnson, B.A., McCall, M.A., Morgans, C.W., Nusinowitz, S., Peachey, N.S., Rice, D.S., Vessey, K.A., & Gregg, R.G. (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. Visual Neuroscience 23, 11–24.CrossRefGoogle Scholar
Claes, E., Seeliger, M., Michalakis, S., Biel, M., Humphries, P., & Haverkamp, S. (2004). Morphological characterization of the retina of the CNGA3(−/−)Rho(−/−) mutant mouse lacking functional cones and rods. Investigative Ophthalmology and Visual Science 45, 2039–2048.CrossRefGoogle Scholar
Dhingra, A., Jiang, M., Wang, T.L., 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 Galpha(o). Journal of Neuroscience 22, 4878–4884.Google Scholar
Dhingra, A., Lyubarsky, A., Jiang, M., Pugh, E.N., Jr., Birnbaumer, L., Sterling, P., & Vardi, N. (2000). The light response of ON bipolar neurons requires G[alpha]o. Journal of Neuroscience 20, 9053–9058.Google Scholar
Dick, O., Tom Dieck, S., Altrock, W.D., Ammermuller, J., Weiler, R., Garner, C.C., Gundelfinger, E.D., & Brandstatter, J.H. (2003). The presynaptic active zone protein bassoon is essential for photoreceptor ribbon synapse formation in the retina. Neuron 37, 775–786.CrossRefGoogle Scholar
Goldowitz, D., Frankel, W.N., Takahashi, J.S., Holtz-Vitaterna, M., Bult, C., Kibbe, W.A., Snoddy, J., Li, Y., Pretel, S., Yates, J., & Swanson, D.J. (2004). Large-scale mutagenesis of the mouse to understand the genetic bases of nervous system structure and function. Brain Research. Molecular Brain Research 132, 105–115.CrossRefGoogle Scholar
Grayson, C., Reid, S.N., Ellis, J.A., Rutherford, A., Sowden, J.C., Yates, J.R., Farber, D.B., & Trump, D. (2000). Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri-Rb1 cells. Human Molecular Genetics 9, 1873–1879.CrossRefGoogle Scholar
Haeseleer, F., Imanishi, Y., Maeda, T., Possin, D.E., 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 Neuroscience 7, 1079–1087.Google Scholar
Hood, D.C. & Birch, D.G. (1996). Beta wave of the scotopic (rod) electroretinogram as a measure of the activity of human on-bipolar cells. Journal of the Optical Society of America A. Optics, Image Science, and Vision 13, 623–633.CrossRefGoogle Scholar
Jablonski, M.M., Dalke, C., Wang, X., Lu, L., Manly, K.F., Pretsch, W., Favor, J., Pardue, M.T., Rinchik, E.M., Williams, R.W., Goldowitz, D., & Graw, J. (2005a). An ENU-induced mutation in Rs1h causes disruption of retinal structure and function. Molecular Vision 11, 569–581.Google Scholar
Jablonski, M.M., Wang, X., Lu, L., Miller, D.R., Rinchik, E.M., Williams, R.W., & Goldowitz, D. (2005b). The Tennessee Mouse Genome Consortium: identification of ocular mutants. Visual Neuroscience 22, 595–604.Google Scholar
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.Google Scholar
Lenzi, D. & Von Gersdorff, H. (2001). Structure suggests function: the case for synaptic ribbons as exocytotic nanomachines. Bioessays 23, 831–840.CrossRefGoogle Scholar
Mansergh, F., Orton, N.C., Vessey, J.P., Lalonde, M.R., Stell, W.K., Tremblay, F., Barnes, S., Rancourt, D.E., & Bech-Hansen, N.T. (2005). Mutation of the calcium channel gene Cacna1f disrupts calcium signaling, synaptic transmission and cellular organization in mouse retina. Human Molecular Genetics 14, 3035–3046.CrossRefGoogle Scholar
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 mGluR6 gene. Cell 80, 757–765.CrossRefGoogle Scholar
Molday, L.L., Hicks, D., Sauer, C.G., Weber, B.H., & Molday, R.S. (2001). Expression of X-linked retinoschisis protein RS1 in photoreceptor and bipolar cells. Investigative Ophthalmology and Visual Science 42, 816–825.Google Scholar
Morgans, C.W., Bayley, P.R., Oesch, N.W., Ren, G., Akileswaran, L., & Taylor, W.R. (2005). Photoreceptor calcium channels: Insight from night blindness. Visual Neuroscience 22, 561–568.CrossRefGoogle Scholar
Murayama, K., Kuo, C.Y., & Sieving, P.A. (1991). Abnormal threshold ERG response in X-linked juvenile retinoschisis: Evidence or a proximal retinal origin of the human STR. Clinical Visual Science 6, 317–322.Google Scholar
Nomura, A., Shigemoto, R., Nakamura, Y., Okamoto, N., Mizuno, N., & Nakanishi, S. (1994). Developmentally regulated postsynaptic localization of a metabotropic glutamate receptor in rat rod bipolar cells. Cell 77, 361–369.CrossRefGoogle Scholar
Park, S.J., Oh, S.J., Chung, J.W., & Chun, M.H. (2002). Tolerance of horizontal cells to excitotoxicity in the developing FVB/N mouse retina. Neuroreport 13, 2091–2095.CrossRefGoogle Scholar
Peichl, L. & Gonzalez-Soriano, J. (1993). Unexpected presence of neurofilaments in axon-bearing horizontal cells of the mammalian retina. Journal of Neuroscience 13, 4091–4100.Google Scholar
Peichl, L. & Gonzalez-Soriano, J. (1994). Morphological types of horizontal cell in rodent retinae: A comparison of rat, mouse, gerbil, and guinea pig. Visual Neuroscience 11, 501–517.CrossRefGoogle Scholar
Piatigorsky, J. (2001). Dual use of the transcriptional repressor (CtBP2)/ribbon synapse (RIBEYE) gene: How prevalent are multifunctional genes? Trends in Neurosciences 24, 555–557.Google Scholar
Pinto, L.H. & Enroth-Cugell, C. (2000). Tests of the mouse visual system. Mammalian Genome 11, 531–536.CrossRefGoogle Scholar
Pinto, L.H., Vitaterna, M.H., Siepka, S.M., Shimomura, K., Lumayag, S., Baker, M., Fenner, D., Mullins, R.F., Sheffield, V.C., Stone, E.M., Heffron, E., & Takahashi, J.S. (2004). Results from screening over 9000 mutation-bearing mice for defects in the electroretinogram and appearance of the fundus. Vision Research 44, 3335–3345.CrossRefGoogle Scholar
Reid, S.N., Akhmedov, N.B., Piriev, N.I., Kozak, C.A., Danciger, M., & Farber, D.B. (1999). The mouse X-linked juvenile retinoschisis cDNA: Expression in photoreceptors. Gene 227, 257–266.CrossRefGoogle Scholar
The Retinosis Consortium (1998). Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis. The Retinoschisis Consortium. Human Molecular Genetics 7, 1185–1192.CrossRefGoogle 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.CrossRefGoogle Scholar
Sauer, C.G., Gehrig, A., Warneke-Wittstock, R., Marquardt, A., Ewing, C.C., Gibson, A., Lorenz, B., Jurklies, B., & Weber, B.H. (1997). Positional cloning of the gene associated with X-linked juvenile retinoschisis. Nature Genetics 17, 164–170.CrossRefGoogle Scholar
Shelley, J., Dedek, K., Schubert, T., Feigenspan, A., Schultz, K., Hombach, S., Willecke, K., & Weiler, R. (2006). Horizontal cell receptive fields are reduced in connexin57-deficient mice. European Journal of Neuroscience 23, 3176–3186.CrossRefGoogle Scholar
Strettoi, E., Mears, A.J., & Swaroop, A. (2004). Recruitment of the rod pathway by cones in the absence of rods. Journal of Neuroscience 24, 7576–7582.Google 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.Google Scholar
Tagawa, Y., Sawai, H., Ueda, Y., Tauchi, M., & Nakanishi, S. (1999). Immunohistological studies of metabotropic glutamate receptor subtype 6-deficient mice show no abnormality of retinal cell organization and ganglion cell maturation. Journal of Neuroscience 19, 2568–2579.Google Scholar
Takada, Y., Fariss, R.N., Tanikawa, A., Zeng, Y., Carper, D., Bush, R., & Sieving, P.A. (2004). A retinal neuronal developmental wave of retinoschisin expression begins in ganglion cells during layer formation. Investigative Ophthalmology and Visual Science 45, 3302–3312.CrossRefGoogle Scholar
Von Gersdorff, H. (2001). Synaptic ribbons: Versatile signal transducers. Neuron 29, 7–10.CrossRefGoogle Scholar
Wang, P., Yang, G., Mosier, D.R., Chang, P., Zaidi, T., Gong, Y.D., Zhao, N.M., Dominguez, B., Lee, K.F., Gan, W.B., & Zheng, H. (2005). Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-Like protein 2. Journal of Neuroscience 25, 1219–1225.Google Scholar
Weber, B.H., Schrewe, H., Molday, L.L., Gehrig, A., White, K.L., Seeliger, M.W., Jaissle, G.B., Friedburg, C., Tamm, E., & Molday, R.S. (2002). Inactivation of the murine X-linked juvenile retinoschisis gene, Rs1h, suggests a role of retinoschisin in retinal cell layer organization and synaptic structure. Proceedings of the National Academy of Sciences of the United States of America 99, 6222–6227.CrossRefGoogle Scholar
Zeng, Y., Takada, Y., Kjellstrom, S., Hiriyanna, K., Tanikawa, A., Wawrousek, E., Smaoui, N., Caruso, R., Bush, R.A., & Sieving, P.A. (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. Investigative Ophthalmology and Visual Science 45, 3279–3285.CrossRefGoogle Scholar