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

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.

Effects of Dopamine D2-Like Receptor Antagonists on Light Responses of Ganglion Cells in Wild-Type and P23H Rat Retinas

“…The finding in the present study that the D2/D3 receptor antagonists sulpiride and eticlopride transform long-latency ON-center cells into OFF-center cells suggests that these cells might have at one time been actually OFF-center cells. In retrospect this would account for the observations in my earlier studies [ 32 , 40 ] that OFF-center cells were encountered less frequently than ON-center cells in P23H rat retinas.…”

“…These cells can easily be missed if the retina is stimulated with a brief (e.g., 100 ms) flash of light, in which case these long-latency cells could appear to be OFF-center cells. Although in my previous electrophysiological studies in the P23H rat retina [ 32 , 40 ] I used long-duration flashes at the beginning of an experiment to classify cells as either ON- or OFF-center, it was assumed at the time that these long-latency cells were ‘unhealthy’ ON-center cells, recorded in areas of the retina that had perhaps undergone a greater degree of degeneration. The finding in the present study that the D2/D3 receptor antagonists sulpiride and eticlopride transform long-latency ON-center cells into OFF-center cells suggests that these cells might have at one time been actually OFF-center cells.…”

Effects of GABACR and mGluR1 antagonists on contrast response functions of Sprague-Dawley and P23H rat retinal ganglion cells

“…I previously found that both TPMPA and JNJ16259685 increase the sensitivity of P23H rat RGCs to brief flashes of light, shifting the intensity-response curves to the left [ 19 , 20 ]. A leftward shift of the intensity-response curve is equivalent to removing a neutral density filter in front of the light source.…”

“…TPMPA would eliminate this GABA-mediated inhibition and thus the attenuation of light-evoked excitatory potentials in the axon terminals of bipolar cells. Previously, I reported that the effects of JNJ16259685 on the responses of P23H rat RGCs to flashes of light are similar to those of TPMPA [ 20 ]. I had postulated that the effects of JNJ16259685 may be mediated through a reduction in release of GABA onto GABA C receptors.…”

“…Previously, I showed that the GABA C R antagonist TPMPA and the mGluR1 antagonist JNJ16259685 increase the sensitivity of retinal ganglion cells (RGCs) in the P23H rat model of retinitis pigmentosa to brief flashes of light [ 19 , 20 ]. The effects of these receptor antagonists are likely due to actions on cells in the inner retina since the receptors for these antagonists are found predominately on cell processes within the inner retina [ 21 , 22 ].…”