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 Grm6(nob3)). Immunohistochemistry of the Grm6(nob3) retina showed that GRM6 was absent. The ERG and visual behaviour abnormalities of Grm6(nob3) mice are similar to Grm6(nob4) animals, and similar deficits were seen in compound heterozygotes (Grm6(nob4/nob3)), indicating that Grm6(nob3) is allelic to Grm6(nob4). Visual responses of Grm6(nob3) retinal ganglion cells (RGCs) to light onset were abnormal. Grm6(nob3) ON RGCs were rarely recorded, but when they were, had ill-defined receptive field (RF) centres and delayed onset latencies. When Grm6(nob3) OFF-centre RGC responses were evoked by full-field stimulation, significantly fewer converted that response to OFF/ON compared to Grm6(nob4) RGCs. Grm6(nob4/nob3) RGC responses verified the conclusion that the two mutants are allelic. We propose that Grm6(nob3) is a new model of human autosomal recessive congenital stationary night blindness. However, an allelic difference between Grm6(nob3) and Grm6(nob4) 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.
Subject(s)
Receptors, Metabotropic Glutamate/genetics , Retinal Ganglion Cells/physiology , Alleles , Amino Acid Sequence , Animals , Chromosome Mapping , Electroretinography , Mice , Mice, Inbred C57BL , Molecular Sequence Data , Mutation , Photic Stimulation , Receptors, Metabotropic Glutamate/metabolism , Retina/anatomy & histology , Retina/metabolism , Sequence Analysis, DNA , Visual FieldsABSTRACT
PURPOSE: Subretinal prosthetics are designed to electrically stimulate second-order cells, replacing dysfunctional photoreceptors in diseases such as retinitis pigmentosa (RP). For functional vision to occur, this signal must also reach central visual structures. In the current study, a subretinally implanted prosthetic was evaluated in the Royal College of Surgeons (RCS) rat model of RP, to determine its capacity to activate the retinotectal pathway. METHODS: Prosthetic implants were placed in RCS and wild-type (WT) rats at 4 weeks of age and evaluated 3 months later. Control rats underwent sham surgery, implantation with inactive prosthetics, or no treatment. Implant- and visible-evoked responses were isolated and evaluated in the superior colliculus (SC). RESULTS: In WT and RCS rats with active prosthetics, implant-driven responses were found in 100% of WT and 64% of RCS rats and were confined to a small SC region that corresponded to the retinal sector containing the implant and differed from visible-evoked responses. In addition, visible-evoked responses were more robust at sites that received implant input compared to sites that did not. These effects were not seen in WT rats or RCS control animals; although a general trophic effect on the number of responsive sites was observed in all RCS rats with surgery compared to untreated RCS rats. CONCLUSIONS: Direct activation of the retina by a subretinal implant induces activity in the SC of RCS rats, suggesting that these implants have some capacity to replace dysfunctional photoreceptors. The data also provide evidence for implant-induced neurotrophic effects as a consequence of both its presence and its activity in the retina.
