Effects of GABA receptor antagonists on thresholds of P23H rat retinal ganglion cells to electrical stimulation of the retina
ABSTRACT An electronic retinal prosthesis may provide useful vision for patients suffering from retinitis pigmentosa (RP). In animal models of RP, the amount of current needed to activate retinal ganglion cells (RGCs) is higher than in normal, healthy retinas. In this study, we sought to reduce the stimulation thresholds of RGCs in a degenerate rat model (P23H-line 1) by blocking GABA receptor mediated inhibition in the retina. We examined the effects of TPMPA, a GABA(C) receptor antagonist, and SR95531, a GABA(A) receptor antagonist, on the electrically evoked responses of RGCs to biphasic current pulses delivered to the subretinal surface through a 400 µm diameter electrode. Both TPMPA and SR95531 reduced the stimulation thresholds of ON-center RGCs on average by 15% and 20% respectively. Co-application of the two GABA receptor antagonists had the greatest effect, on average reducing stimulation thresholds by 32%. In addition, co-application of the two GABA receptor antagonists increased the magnitude of the electrically evoked responses on average three-fold. Neither TPMPA nor SR95531, applied alone or in combination, had consistent effects on the stimulation thresholds of OFF-center RGCs. We suggest that the effects of the GABA receptor antagonists on ON-center RGCs may be attributable to blockage of GABA receptors on the axon terminals of ON bipolar cells.
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ABSTRACT: Electronic retinal prostheses are being developed for people who become blind due to loss of photoreceptors from the disease retinitis pigmentosa. Previously, we reported on the responses of RGCs in the P23H rat (a model of retinitis pigmentosa) and the Sprague-Dawley (SD) rat to stimulation with a 400-μm diameter electrode (Jensen and Rizzo, 2011). With recent clinical trials now utilizing smaller (50-200 μm) electrodes, I sought to investigate the electrically evoked responses of RGCs in P23H and SD rat retinas with a smaller (125-μm diameter) electrode. Here, I report on the electrically evoked spike activity from RGCs that arose from stimulation of the retinal neural network. With biphasic current pulses of 1 ms per phase, the thresholds for activation of SD rat RGCs ranged from 0.52 to 2.8 μA; thresholds of P23H rat RGCs ranged from 1.2 to 7.8 μA. Median thresholds of RGCs were 1.4 μA in SD rats and 2.5 μA in P23H rats. These thresholds measurements were obtained with the recording electrode placed over the stimulating electrode. I also examined how thresholds of RGCs change as a function of distance (100-500 μm) from the center of the stimulating electrode. The median threshold currents of RGCs were much higher in P23H rats for all distances. What was striking was that the thresholds for activation of RGCs in P23H rat retinas rose much more rapidly. When the recording electrode was only 100-200 μm from the center of the stimulating electrode, the median threshold current of P23H rat RGCs rose by 460%. In contrast, the median threshold current of SD rat RGCs increased only 29%. I also investigated the contribution of photoreceptors to the electrically evoked responses of ON-center RGCs in SD rat retinas by examining the change in RGC thresholds when photoreceptor input to ON bipolar cells was blocked with the mGluR6 antagonist CPPG. At 500-600 μm, CPPG suppressed the light-evoked responses of the RGCs and at the same time increased the amount of current needed to generate an electrically evoked response. Similar to what was observed with SD rat RGCs, CPPG suppressed the light-evoked responses of ON-center P23H rat RGCs. However, the stimulation thresholds were not significantly altered. In conclusion, the data show that the threshold currents for indirect stimulation of both SD and P23H rat RGCs with a 125-μm diameter electrode are much lower than what we found previously with a 400-μm diameter electrode. To achieve high resolution vision with a multielectrode array, the spread of activation of RGCs needs to be limited. Our findings indicate that the spread of activation of RGCs is more confined in the degenerate retina. Lastly, my findings indicate that photoreceptors contribute to the lower stimulation thresholds of RGCs in normal, healthy retinas.Experimental Eye Research 04/2012; 99:71-7. DOI:10.1016/j.exer.2012.03.016 · 3.02 Impact Factor
Article: Electrical Induction of Vision.[Show abstract] [Hide abstract]
ABSTRACT: We assess what monkeys see during electrical stimulation of primary visual cortex (area V1) and relate the findings to visual percepts evoked electrically from human V1. Discussed are: (1) the electrical, cytoarchitectonic, and visuo-behavioural factors that affect the ability of monkeys to detect currents in V1; (2) the methods used to ascertain what monkeys see when electrical stimulation is delivered to V1; (3) a corticofugal mechanism for the induction of visual percepts; and (4) the quantity of information transferred to V1 by electrical stimulation. Experiments are proposed that should advance our understanding of how electrical stimulation affects macaque and human V1. This work contributes to the development of a cortical visual prosthesis for the blind. We dedicate this work to the late Robert W. Doty.Neuroscience & Biobehavioral Reviews 03/2013; DOI:10.1016/j.neubiorev.2013.03.012 · 10.28 Impact Factor
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ABSTRACT: Electrical stimulation of retinal neurons with an advanced retinal prosthesis may eventually provide high-resolution artificial vision to the blind. However, the success of future prostheses depends on the ability to activate the major parallel visual pathways of the human visual system. Electrical stimulation of the five numerically dominant retinal ganglion cell types was investigated by simultaneous stimulation and recording in isolated peripheral primate (Macaca sp.) retina using multi-electrode arrays. ON and OFF midget, ON and OFF parasol, and small bistratified ganglion cells could all be activated directly to fire a single spike with submillisecond latency using brief pulses of current within established safety limits. Thresholds for electrical stimulation were similar in all five cell types. In many cases, a single cell could be specifically activated without activating neighboring cells of the same type or other types. These findings support the feasibility of direct electrical stimulation of the major visual pathways at or near their native spatial and temporal resolution.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2013; 33(17):7194-205. DOI:10.1523/JNEUROSCI.4967-12.2013 · 6.75 Impact Factor