Electrically-evoked responses for retinal prostheses are differentially altered depending on ganglion cell types in outer retinal neurodegeneration caused by Crb1 gene mutation

Abstract

BackgroundMicroelectronic prostheses for artificial vision stimulate neurons surviving outer retinal neurodegeneration such as retinitis pigmentosa (RP). Yet, the quality of prosthetic vision substantially varies across subjects, maybe due to different levels of retinal degeneration and/or distinct genotypes. Although the RP genotypes are remarkably diverse, prosthetic studies have primarily used retinal degeneration (rd) 1 and 10 mice, which both have Pde6b gene mutation. Here, we report the electric responses arising in retinal ganglion cells (RGCs) of the rd8 mouse model which has Crb1 mutation.MethodsWe first investigated age-dependent histological changes of wild-type (wt), rd8, and rd10 mice retinas by H&E staining. Then, we used cell-attached patch clamping to record spiking responses of ON, OFF and direction selective (DS) types of RGCs to a 4-ms-long electric pulse. The electric responses of rd8 RGCs were analyzed in comparison with those of wt RGCs in terms of individual RGC spiking patterns, populational characteristics, and spiking consistency across trials.ResultsIn the histological examination, the rd8 mice showed partial retinal foldings, but the outer nuclear layer thicknesses remained comparable to those of the wt mice, indicating the early-stage of RP. Although spiking patterns of each RGC type seemed similar to those of the wt retinas, correlation levels between electric vs. light response features were different across the two mouse models. For example, in comparisons between light vs. electric response magnitudes, ON/OFF RGCs of the rd8 mice showed the same/opposite correlation polarity with those of wt mice, respectively. Also, the electric response spike counts of DS RGCs in the rd8 retinas showed a positive correlation with their direction selectivity indices (r = 0.40), while those of the wt retinas were negatively correlated (r = −0.90). Lastly, the spiking timing consistencies of late responses were largely decreased in both ON and OFF RGCs in the rd8 than the wt retinas, whereas no significant difference was found across DS RGCs of the two models.ConclusionOur results indicate the electric response features are altered depending on RGC types even from the early-stage RP caused by Crb1 mutation. Given the various degeneration patterns depending on mutation genes, our study suggests the importance of both genotype- and RGC type-dependent analyses for retinal prosthetic research.

Retinal Prostheses: Engineering and Clinical Perspectives for Vision Restoration

“…Individualized electrical stimuli from the independent electrodes on MEAs can be used to target different types of cells, such as ON-and OFF-cells. Moreover, researchers found that the response to an electric pulse produced by RGCs is also dependent on the patient disease genotype [51]. Patients with varying genotypes of retinitis pigmentosa would, therefore, have varying quality of prosthetic vision, even though the same device may be implanted in all patients.…”

Effects on Retinal Stimulation of the Geometry and the Insertion Location of Penetrating Electrodes

“…9), each sublamina may be accurately targeted using the electrodes we simulated here, potentially improving the performance of retinal prostheses by more preferential activation of either ON or OFF pathway. However, it would be considerably challenging in the degenerate retinas in which the laminar structure is altered [68,69]. Along with previous efforts of stimulation parameter optimization for the enhanced selective activation [58,59,[63][64][65][66][67], the hardware approach such as the accurate positioning of penetrating electrodes may further advance discriminate activation of ON or OFF pathway.…”

“…This limitation is expected to be easily overcome if reliable information becomes available, as our framework can readily accommodate anisotropic conductivities. Moreover, the retinal degeneration substantially alters not only RGC spiking patterns [68,70] but also anatomical structures of the retina [68,69], which is highly likely to change the spatial conductivity properties of the retina. Therefore, it is essential to precisely measure electrical conductivities of each retinal > REPLACE THIS LINE WITH YOUR PAPER IDENTIFICATION NUMBER (DOUBLE-CLICK HERE TO EDIT) < 8 layers.…”