title: Activation of ganglion cells in wild-type and P23H rat retinas with a small subretinal electrode.
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.
authors.affiliation: VA Boston Healthcare System, Mail Stop 151E, 150 South Huntington Avenue, Boston, MA 02130, USA. Ralph.jensen@va.gov
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: Jensen
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005074:Evoked Potentials, Visual / Q000502:physiology*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D008839:Microelectrodes; D010775:Photic Stimulation; D020419:Photoreceptor Cells, Vertebrate / Q000502:physiology* / Q000528:radiation effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000502:physiology*; D012174:Retinitis Pigmentosa / Q000378:metabolism*; D012684:Sensory Thresholds / Q000502:physiology
chemical_list: D018094:Receptors, Metabotropic Glutamate; C104331:cyclopropyl-4-phosphonophenylglycine; D005998:Glycine