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      Cone ERG Changes During Light Adaptation in Two All-Cone Mutant Mice: Implications for Rod-Cone Pathway Interactions

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          Abstract

          Purpose

          The b-wave of the cone ERG increases in amplitude and speed during the first few minutes of adaptation to a rod-suppressing background light. Earlier studies implicate rod pathway input to the cone pathway in these changes.

          Methods

          The timing and amplitude of the cone b-wave and isolated oscillatory potentials (OP) during the first 10 minutes of light adaptation in wild-type (WT) mice and two mutant lines without functional rods was examined: rhodopsin knockout ( Rho −/− ), lacking rod outer segments, and NRL knockout ( Nrl −/− ), in which rods are replaced by S-cones. Expression of the immediate-early gene c-fos, which is increased in the inner retina by light-induced activity, was evaluated by immunohistochemistry in dark- and light-adapted retinas.

          Results

          WT b-wave and OP amplitudes increased, and implicit times decreased during light adaptation. Subtracting OP did not alter b-wave changes. Rho −/− b-wave and OP amplitudes did not increase during adaptation. B-wave timing and amplitude and the timing of the major OP at 1 minute of adaptation were equivalent to WT at 10 minutes. The light-adapted ERG b-wave in Nrl −/− mice, which originates in both the rod and cone pathways, changed in absolute amplitude and timing similar to WT. C-fos expression was present in the inner retinas of dark-adapted Rho −/− but not WT or Nrl −/− mice.

          Conclusions

          Activity in the distal rod pathway produces changes in the cone ERG during light adaptation. Rods in Rho −/− mice constitutively activate this rod-cone pathway interaction. The rod pathway S-cones in Nrl −/− mice may maintain the WT interaction.

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          Most cited references34

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          Oscillatory potentials in the retina: what do they reveal.

          This chapter is an overview of current knowledge on the oscillatory potentials (OPs) of the retina. The first section describes the characteristics of the OPs. The basic, adaptational, pharmacological and developmental characteristics of the OPs are different from the a- and b-waves, the major components of the electroretinogram (ERG). The OPs are most easily recorded in mesopic adaptational conditions and reflect rapid changes of adaptation. They represent photopic and scotopic processes, probably an interaction between cone and rod activity in the retina. The OPs are sensitive to disruption of inhibitory (dopamine, GABA-, and glycine-mediated) neuronal pathways and are not selectively affected by excitatory amino acids. The earlier OPs are associated with the on-components and the late OPs with the off-components in response to a brief stimulus of light. The postnatal appearance of the first oscillatory activity is preceded by the a- and b-waves. The earlier OPs appear postnatally prior to, and mature differently from, the later ones. The second section deals with present views on the origin of the OPs. These views are developed from experimental studies with the vertebrate retina including the primate retina and clinical studies. Findings favor the conclusion that the OPs reflect neuronal synaptic activity in inhibitory feedback pathways initiated by the amacrines in the inner retina. The bipolar (or the interplexiform) cells are the probable generators of the OPs. Dopaminergic neurons, probably amacrines (or interplexiform cells), are involved in the generation of the OPs. The earlier OPs are generated in neurons related to the on-pathway of the retina and the later ones to the off-channel system. Peptidergic neurons may be indirectly involved as modulators. The individual OPs seem to represent the activation of several retinal generators. The earlier OPs are more dependent on an intact rod function and the later ones on an intact cone system. Thus, the OPs are good indicators of neuronal adaptive mechanisms in the retina and are probably the only post-synaptic neuronal components that can be recorded in the ERG except when structured stimuli are used. The last section describes the usefulness of the oscillatory response as an instrument to study the postnatal development of neuronal adaptation of the retina. In this section clinical examples of of the sensitivity of the OPs for revealing early disturbance in neuronal function in different retinal diseases such as pediatric, vascular and degenerative retinopathies are also given.
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            Retinopathy induced in mice by targeted disruption of the rhodopsin gene.

            Retinitis pigmentosa (RP) represents the most common mendelian degenerative retinopathy of man, involving death of rod photoreceptors, cone cell degeneration, retinal vessel attenuation and pigmentary deposits. The patient experiences night blindness, usually followed by progressive loss of visual field. Genetic linkage between an autosomal dominant RP locus and rhodopsin, the photoreactive pigment of the rod cells, led to the identification of mutations within the rhodopsin gene in both dominant and recessive forms of RP. To better understand the functional and structural role of rhodopsin in the normal retina and in the pathogenesis of retinal disease, we generated mice carrying a targeted disruption of the rhodopsin gene. Rho-/- mice do not elaborate rod outer segments, losing their photoreceptors over 3 months. There is no rod ERG response in 8-week-old animals. Rho+/- animals retain the majority of their photoreceptors although the inner and outer segments of these cells display some structural disorganization, the outer segments becoming shorter in older mice. These animals should provide a useful genetic background on which to express other mutant opsin transgenes, as well as a model to assess the therapeutic potential of re-introducing functional rhodopsin genes into degenerating retinal tissues.
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              Phototransduction in transgenic mice after targeted deletion of the rod transducin alpha -subunit.

              Retinal photoreceptors use the heterotrimeric G protein transducin to couple rhodopsin to a biochemical cascade that underlies the electrical photoresponse. Several isoforms of each transducin subunit are present in the retina. Although rods and cones seem to contain distinct transducin subunits, it is not known whether phototransduction in a given cell type depends strictly on a single form of each subunit. To approach this question, we have deleted the gene for the rod transducin alpha-subunit in mice. In hemizygous knockout mice, there was a small reduction in retinal transducin alpha-subunit content but retinal morphology and the physiology of single rods were largely normal. In homozygous knockout mice, a mild retinal degeneration occurred with age. Rod-driven components were absent from the electroretinogram, whereas cone-driven components were retained. Every photoreceptor examined by single-cell recording failed to respond to flashes, with one exception. The solitary responsive cell was insensitive, as expected for a cone, but had a rod-like spectral sensitivity and flash response kinetics that were slow, even for rods. These results indicate that most if not all rods use a single transducin type in phototransduction.
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                Author and article information

                Journal
                Invest Ophthalmol Vis Sci
                Invest. Ophthalmol. Vis. Sci
                iovs
                Invest Ophthalmol Vis Sci
                IOVS
                Investigative Ophthalmology & Visual Science
                The Association for Research in Vision and Ophthalmology
                0146-0404
                1552-5783
                August 2019
                : 60
                : 10
                : 3680-3688
                Affiliations
                [1 ]National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, United States
                [2 ]Department of Ophthalmology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
                [3 ]National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States
                Author notes
                Correspondence: Ronald A. Bush, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, 50 South Drive, MSC 8021, Bethesda, MD 20892, USA; bushr@ 123456nidcd.nih.gov .
                Article
                iovs-60-08-54 IOVS-19-27242R1
                10.1167/iovs.19-27242
                6716952
                31469895
                c453a5c5-113e-4e76-bcbb-7e8d422a6446
                Copyright 2019 The Authors

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                History
                : 10 April 2019
                : 15 July 2019
                Categories
                Retina

                electroretinogram,rod-cone interaction,light adaptation,cones,oscillatory potentials

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