Allelic variance between GRM6 mutants, Grm6nob3 and Grm6nob4 results in differences in retinal ganglion cell visual responses

Dennis M. Maddox, Kirstan A. Vessey, Gary L. Yarbrough, Brandon M. Invergo, Donald R. Cantrell, Samsoon Inayat, Victoria Balannik, Wanda L. Hicks, Norman L. Hawes, Shannon Byers, Richard S. Smith, Ron Hurd, Douglas Howell, Ronald G. Gregg, Bo Chang, Jürgen K. Naggert, John B. Troy, Lawrence H. Pinto, Patsy M. Nishina, Maureen A. McCall*

*Corresponding author for this work

Research output: Contribution to journalArticle

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Abstract

An electroretinogram (ERG) screen identified a mouse with a normal a-wave but lacking a b-wave, and as such it was designated no b-wave3 (nob3). The nob3 phenotype mapped to chromosome 11 in a region containing the metabotropic glutamate receptor 6 gene (Grm6). Sequence analyses of cDNA identified a splicing error in Grm6, introducing an insertion and an early stop codon into the mRNA of affected mice (designated Grm6nob3). Immunohistochemistry of the Grm6nob3 retina showed that GRM6 was absent. The ERG and visual behaviour abnormalities of Grm6nob3 mice are similar to Grm6nob4 animals, and similar deficits were seen in compound heterozygotes (Grm6nob4/nob3), indicating that Grm6nob3 is allelic to Grm6nob4. Visual responses of Grm6nob3 retinal ganglion cells (RGCs) to light onset were abnormal. Grm6nob3 ON RGCs were rarely recorded, but when they were, had ill-defined receptive field (RF) centres and delayed onset latencies. When Grm6nob3 OFF-centre RGC responses were evoked by full-field stimulation, significantly fewer converted that response to OFF/ON compared to Grm6nob4 RGCs. Grm6nob4/nob3 RGC responses verified the conclusion that the two mutants are allelic. We propose that Grm6nob3 is a new model of human autosomal recessive congenital stationary night blindness. However, an allelic difference between Grm6nob3 and Grm6nob4 creates a disparity in inner retinal processing. Because the localization of GRM6 is limited to bipolar cells in the On pathway, the observed difference between RGCs in these mutants is likely to arise from differences in their inputs.

Original languageEnglish (US)
Pages (from-to)4409-4424
Number of pages16
JournalJournal of Physiology
Volume586
Issue number18
DOIs
StatePublished - 2008

ASJC Scopus subject areas

  • Physiology

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    Maddox, D. M., Vessey, K. A., Yarbrough, G. L., Invergo, B. M., Cantrell, D. R., Inayat, S., Balannik, V., Hicks, W. L., Hawes, N. L., Byers, S., Smith, R. S., Hurd, R., Howell, D., Gregg, R. G., Chang, B., Naggert, J. K., Troy, J. B., Pinto, L. H., Nishina, P. M., & McCall, M. A. (2008). Allelic variance between GRM6 mutants, Grm6nob3 and Grm6nob4 results in differences in retinal ganglion cell visual responses. Journal of Physiology, 586(18), 4409-4424. https://doi.org/10.1113/jphysiol.2008.157289