Effects of a Metabotropic Glutamate 1 Receptor Antagonist on Light Responses of Retinal Ganglion Cells in a Rat Model of Retinitis Pigmentosa

Ralph J Jensen

doi:10.1371/journal.pone.0079126

Abstract

BackgroundRetinitis pigmentosa (RP) is a progressive retinal degenerative disease that causes deterioration of rod and cone photoreceptors. A well-studied animal model of RP is the transgenic P23H rat, which carries a mutation in the rhodopsin gene. Previously, I reported that blocking retinal GABAC receptors in the P23H rat increases light responsiveness of retinal ganglion cells (RGCs). Because activation of metabotropic glutamate 1 (mGlu1) receptors may enhance the release of GABA onto GABAC receptors, I examined the possibility that blocking retinal mGlu1 receptors might in itself increase light responsiveness of RGCs in the P23H rat.Methodology/Principal FindingsElectrical recordings were made from RGCs in isolated P23H rat retinas. Spike activity of RGCs was measured in response to brief flashes of light over a range of light intensities. Intensity-response curves were evaluated prior to and during bath application of the mGlu1 receptor antagonist JNJ16259685. I found that JNJ16259685 increased light sensitivity of all ON-center RGCs and most OFF-center RGCs studied. RGCs that were least sensitive to light showed the greatest JNJ16259685-induced increase in light sensitivity. On average, light sensitivity increased in ON-center RGCs by 0.58 log unit and in OFF-center RGCs by 0.13 log unit. JNJ16259685 increased the maximum peak response of ON-center RGCs by 7% but had no significant effect on the maximum peak response of OFF-center RGCs. The effects of JNJ16259685 on ON-center RGCs were occluded by a GABAC receptor antagonist.ConclusionsThe results of this study indicate that blocking retinal mGlu1 receptors in a rodent model of human RP potentiates transmission of any, weak signals originating from photoreceptors. This augmentation of photoreceptor-mediated signals to RGCs occurs presumably through a reduction in GABAC-mediated inhibition.

Highlights

Retinitis pigmentosa (RP) is an inherited form of retinal degeneration that affects approximately 1 in 4000 people worldwide
The results of this study indicate that blocking retinal metabotropic glutamate 1 (mGlu1) receptors in a rodent model of human RP potentiates transmission of any, weak signals originating from photoreceptors
In the early stage of RP, patients have difficulty seeing at night due to loss of rod photoreceptors, and this is followed by a progressive loss of daytime vision as cone photoreceptors degenerate

Summary

Introduction

Retinitis pigmentosa (RP) is an inherited form of retinal degeneration that affects approximately 1 in 4000 people worldwide. Mutations in over 40 genes are known to cause RP [1]. Some of these mutations occur within the rhodopsin gene, which is expressed in rod photoreceptors. Retinitis pigmentosa (RP) is a progressive retinal degenerative disease that causes deterioration of rod and cone photoreceptors. A well-studied animal model of RP is the transgenic P23H rat, which carries a mutation in the rhodopsin gene. I reported that blocking retinal GABAC receptors in the P23H rat increases light responsiveness of retinal ganglion cells (RGCs). Because activation of metabotropic glutamate 1 (mGlu1) receptors may enhance the release of GABA onto GABAC receptors, I examined the possibility that blocking retinal mGlu receptors might in itself increase light responsiveness of RGCs in the P23H rat

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Conclusion