Photopic ERG Negative Response from Amacrine Cell Signaling in RCS Rat Retinal Degeneration

Machida, Shigeki; Raz-Prag, Dorit; Fariss, Robert N.; Sieving, Paul A.; Bush, Ronald A.

doi:10.1167/iovs.07-0291

Cited by 70 publications

(61 citation statements)

References 55 publications

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“…18,23 In addition, an increase in the ERG responses from the inner retina (e.g., scotopic threshold response) was also reported in the retina of the aged Royal College of Surgeons rat, a rodent model of retinal degeneration. 24,25 Taken together, inherited retinal diseases associated with progressive photoreceptor degeneration may lead to different types of functional changes in the post-photoreceptoral retinal circuits, including the ON-and OFF pathways, during a relatively early stage of retinal degeneration.…”

Section: Discussionmentioning

confidence: 99%

Photoreceptor and Post-Photoreceptoral Contributions to Photopic ERG a-Wave in Rhodopsin P347L Transgenic Rabbits

Hirota

Kondo

Ueno

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.The a-wave of the photopic electroretinogram (ERG) of macaque monkeys is made up of the electrical activities of cone photoreceptors and post-photoreceptoral neurons. However, it is not known whether the contributions of these two components change in retinas with inherited photoreceptor degeneration. The purpose of this study was to determine the contributions of cones and post-photoreceptoral neurons to the a-wave of the photopic ERGs in rhodopsin Pro347Leu transgenic (Tg) rabbits. METHODS. Ten Tg and 10 wild-type (WT) New Zealand White rabbits were studied at 4 and 12 months of age. The a-waves of the photopic ERGs were elicited by xenon flashes of different stimulus strengths before and after the activities of post-photoreceptoral neurons were blocked by intravitreal injections of a combination of 0.2 to 0.4 mM of 6-cyano-7-nitrouinoxaline-2,3(1H,4H)-dione, disodium (CNQX) and 2 to 4 mM of (Ϯ)-2-amino-4-phosphonobutyric acid. RESULTS. The percentage contribution of the cone photoreceptors to the photopic ERG a-waves increased with increasing stimulus strength, and the percentage ranged from 54% to 75% in 4-month-old WT rabbits. In contrast, the percentage contribution of the cone photoreceptors in 4-month-old Tg rabbits ranged from 32% to 51% (P Ͻ 0.05). The mean percentage contribution of cone photoreceptors became still smaller at 11% to 48% in 12-month-old Tg rabbits. CONCLUSIONS. These results suggest that the relative contribution of cone photoreceptors to the photopic ERG a-wave is smaller in retinas with inherited photoreceptor degeneration. This indicates that the a-waves of the photopic ERGs in patients with retinitis pigmentosa must consider this lower contribution from the cone photoreceptors. (Invest Ophthalmol Vis Sci. 2012;53:1467-1472 The origins of the photopic or light-adapted a-wave of the ERG in macaque monkeys was studied by Sieving et al.3-5 They injected glutamate agonists and antagonists intravitreally to dissect the retinal circuits. They found that the a-wave of the photopic ERG received contributions not only from the cone photoreceptors but also from post-photoreceptoral neurons (e.g., OFF-bipolar cells and horizontal cells) 3,4 because cis-2,3-piperidine dicarboxylic acid (PDA) or kynurenic acid reduced the a-wave amplitude. A later study by Robson et al. 6 showed that the PDA-sensitive post-photoreceptoral a-wave component started at much earlier times of approximately 5 ms in macaques. Frieberg et al.7 also estimated the time course of the cone photoreceptor response in normal human ERGs using the paired-flash technique, in which an intense "probe" flash was delivered at different times after a "test" flash. Their results showed that the photopic ERG a-wave of the human ERG contains an appreciable postphotoreceptoral component, similar to that reported in monkeys. [3][4][5][6] These studies, which were designed to determine the origins of the photopic ERG a-wave, have been performed primarily on normal macaque monkeys and human eyes.3-7 It is not known whether the contr...

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Section: Discussionmentioning

confidence: 99%

Photoreceptor and Post-Photoreceptoral Contributions to Photopic ERG a-Wave in Rhodopsin P347L Transgenic Rabbits

Hirota

Kondo

Ueno

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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“…In providing a sink for extracellular potassium concentration [K + ] o , these channels may contribute directly to currents generating the ERG potentials. Alternatively, their ERG effect could be indirect, through a critical role of Kir2.1 in BC cell synaptic output leading to amacrince and/or ganglion cell activity, which contributes to the STR and PhNR in RCS rat (23,24) and other species (20)(21)(22)40).…”

Section: Discussionmentioning

confidence: 99%

“…IHC was performed in two ways: by conventional application of antibodies to postmortem fixed and sectioned tissue (24) or by in vivo intravitreal application of the Kir-Ab:carrier complex, after which the ERG generally was recorded, and rats were euthanized and enucleated. Eyes were processed by standard methods (24) except that if Kir-Ab had already been administered in vivo, it was not applied to the sections postmortem. In either case, antibodies for double labeling were applied postmortem to fixed sections.…”

Section: Methodsmentioning

confidence: 99%

“…Intraretinal recordings (8) suggest that potassium fluxes in the proximal retina contribute to corneanegative responses in the photopic ERG, homologous to the STR. The STR and PhNR amplitudes are considerably enhanced and easily recorded from the dystrophic Royal College of Surgeons (RCS) rat (23,24), which carries a homozygous Mertk deletion mutation (25) causing slowly progressive outer retinal degeneration (26,27) that subsequently also involves proximal retinal structures (28,29). Building on these observations, we probed Kir channel function in the retina of RCS rat in vivo.…”

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confidence: 99%

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Probing potassium channel function in vivo by intracellular delivery of antibodies in a rat model of retinal neurodegeneration

Raz-Prag

Grimes

Fariss³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Inward rectifying potassium (Kir) channels participate in regulating potassium concentration (K + ) in the central nervous system (CNS), including in the retina. We explored the contribution of Kir channels to retinal function by delivering Kir antibodies (Kir-Abs) into the rat eye in vivo to interrupt channel activity. Kir-Abs were coupled to a peptide carrier to reach intracellular epitopes. Functional effects were evaluated by recording the scotopic threshold response (STR) and photopic negative response (PhNR) of the electroretinogram (ERG) noninvasively with an electrode on the cornea to determine activity of the rod and cone pathways, respectively. Intravitreal delivery of Kir2.1-Ab coupled to the peptide carrier diminished these ERG responses equivalent to dimming the stimulus 10-to 100-fold. Immunohistochemistry (IHC) showed Kir2.1 immunostaining of retinal bipolar cells (BCs) matching the labeling pattern obtained with conventional IHC of applying Kir2.1-Ab to fixed retinal sections postmortem. Whole-cell voltage-clamp BC recordings in rat acute retinal slices showed suppression of bariumsensitive Kir2.1 currents upon inclusion of Kir2.1-Ab in the patch pipette. The in vivo functional and structural results implicate a contribution of Kir2.1 channel activity in these electronegative ERG potentials. Studies with Kir4.1-Ab administered in vivo also suppressed the ERG components and showed immunostaining of Müller cells. The strategy of administering Kir antibodies in vivo, coupled to a peptide carrier to facilitate intracellular delivery, identifies roles for Kir2.1 and Kir4.1 in ERG components arising in the proximal retina and suggests this approach could be of further value in research.Kir | peptide carrier | Pep-1 | retinal bipolar cells | Müller cells

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“…More recently the photopic negative response has been established as a measure of RGC function (Viswanathan et al, 1999), although other cellular origins, such as glia and amacrine cells, have been suggested (Machida et al, 2008). However, at present this has not been assimilated into ISCEV guidelines.…”

Section: Strategies To Measure Functional Outcomementioning

confidence: 99%

Stem Cell Based Therapies for Glaucoma

Jayaram¹,

Becker²,

Limb³

2011

The Mystery of Glaucoma

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Photopic ERG Negative Response from Amacrine Cell Signaling in RCS Rat Retinal Degeneration

Cited by 70 publications

References 55 publications

Photoreceptor and Post-Photoreceptoral Contributions to Photopic ERG a-Wave in Rhodopsin P347L Transgenic Rabbits

Photoreceptor and Post-Photoreceptoral Contributions to Photopic ERG a-Wave in Rhodopsin P347L Transgenic Rabbits

Probing potassium channel function in vivo by intracellular delivery of antibodies in a rat model of retinal neurodegeneration

Stem Cell Based Therapies for Glaucoma

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