Electrical response of retinal ganglion cells in an N-methyl-N-nitrosourea-induced retinal degeneration porcine model

Cha, Seongkwang; Choi, Kwang-Eon; Ahn, Jungryul; Yoo, Minsu; Jeong, Yu-Rim; Kim, Seong-Woo; Goo, Yong Sook

doi:10.1038/s41598-021-03439-w

Cited by 6 publications

(5 citation statements)

References 43 publications

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“…Our results showed that RGCs in the RD retina produced fewer spikes than in the WT retina ( Figure 8 ). In vitro studies using the mouse, rat, and pig models reported that fewer RGC spikes are evoked in the RD retina than in the WT retina with electrical stimulation ( Goo et al, 2011b ; Jensen, 2012 ; Cha et al, 2021 ). In vivo studies in human subjects also showed that higher stimulus intensity was required to induce phosphenes in patients with RP than in people with normal vision ( Delbeke et al, 2001 ; Gekeler et al, 2006 ).…”

Section: Discussionmentioning

confidence: 99%

Stage-Dependent Changes of Visual Function and Electrical Response of the Retina in the rd10 Mouse Model

Cha

Ahn

Jeong

et al. 2022

Front. Cell. Neurosci.

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One of the critical prerequisites for the successful development of retinal prostheses is understanding the physiological features of retinal ganglion cells (RGCs) in the different stages of retinal degeneration (RD). This study used our custom-made rd10 mice, C57BL/6-Pde6bem1(R560C)Dkl/Korl mutated on the Pde6b gene in C57BL/6J mouse with the CRISPR/Cas9-based gene-editing method. We selected the postnatal day (P) 45, P70, P140, and P238 as representative ages for RD stages. The optomotor response measured the visual acuity across degeneration stages. At P45, the rd10 mice exhibited lower visual acuity than wild-type (WT) mice. At P140 and older, no optomotor response was observed. We classified RGC responses to the flashed light into ON, OFF, and ON/OFF RGCs via in vitro multichannel recording. With degeneration, the number of RGCs responding to the light stimulation decreased in all three types of RGCs. The OFF response disappeared faster than the ON response with older postnatal ages. We elicited RGC spikes with electrical stimulation and analyzed the network-mediated RGC response in the rd10 mice. Across all postnatal ages, the spikes of rd10 RGCs were less elicited by pulse amplitude modulation than in WT RGCs. The ratio of RGCs showing multiple peaks of spike burst increased in older ages. The electrically evoked RGC spikes by the pulse amplitude modulation differ across postnatal ages. Therefore, degeneration stage-dependent stimulation strategies should be considered for developing retinal prosthesis and successful vision restoration.

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Section: Discussionmentioning

confidence: 99%

Stage-Dependent Changes of Visual Function and Electrical Response of the Retina in the rd10 Mouse Model

Cha

Ahn

Jeong

et al. 2022

Front. Cell. Neurosci.

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“…This induces a less reliable RGC response to repetitive electrical stimulation ( Ho et al, 2020 ; Yoon et al, 2020 ). Therefore, higher stimulation intensities may be required to electrically activate degenerate RGCs than that required for normal RGCs ( Jensen and Rizzo, 2009 ; Goo et al, 2011b ; Cha et al, 2021 ). However, all previous experiments have focused on the single RGC level response, not the population of RGC responses.…”

Section: Introductionmentioning

confidence: 99%

Correlated Activity in the Degenerate Retina Inhibits Focal Response to Electrical Stimulation

Ahn

Cha

Choi

et al. 2022

Front. Cell. Neurosci.

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Retinal prostheses have shown some clinical success in patients with retinitis pigmentosa and age-related macular degeneration. However, even after the implantation of a retinal prosthesis, the patient’s visual acuity is at best less than 20/420. Reduced visual acuity may be explained by a decrease in the signal-to-noise ratio due to the spontaneous hyperactivity of retinal ganglion cells (RGCs) found in degenerate retinas. Unfortunately, abnormal retinal rewiring, commonly observed in degenerate retinas, has rarely been considered for the development of retinal prostheses. The purpose of this study was to investigate the aberrant retinal network response to electrical stimulation in terms of the spatial distribution of the electrically evoked RGC population. An 8 × 8 multielectrode array was used to measure the spiking activity of the RGC population. RGC spikes were recorded in wild-type [C57BL/6J; P56 (postnatal day 56)], rd1 (P56), rd10 (P14 and P56) mice, and macaque [wild-type and drug-induced retinal degeneration (RD) model] retinas. First, we performed a spike correlation analysis between RGCs to determine RGC connectivity. No correlation was observed between RGCs in the control group, including wild-type mice, rd10 P14 mice, and wild-type macaque retinas. In contrast, for the RD group, including rd1, rd10 P56, and RD macaque retinas, RGCs, up to approximately 400–600 μm apart, were significantly correlated. Moreover, to investigate the RGC population response to electrical stimulation, the number of electrically evoked RGC spikes was measured as a function of the distance between the stimulation and recording electrodes. With an increase in the interelectrode distance, the number of electrically evoked RGC spikes decreased exponentially in the control group. In contrast, electrically evoked RGC spikes were observed throughout the retina in the RD group, regardless of the inter-electrode distance. Taken together, in the degenerate retina, a more strongly coupled retinal network resulted in the widespread distribution of electrically evoked RGC spikes. This finding could explain the low-resolution vision in prosthesis-implanted patients.

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“…Conventionally, it is well-known that a long-duration pulse (over 1000 µs) more effectively induces a network-mediated RGC response due to voltage-gated Ca 2+ channels in BCs [35]. However, our data showed that RGC spikes in RD monkeys and RD pigs [36] were not well induced when we applied a long pulse duration above 1000 µs (Figure 5). We hypothesize that the inhibitory input with GABA by electrically activated surviving horizontal cells (HCs) to BCs and RGCs limits spike firing in the RD.…”

Section: Discussionmentioning

confidence: 53%

The Variation of Electrical Pulse Duration Elicits Reliable Network-Mediated Responses of Retinal Ganglion Cells in Normal, Not in Degenerate Primate Retinas

Cha,

Ahn,

Kim

et al. 2023

Bioengineering

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This study aims to investigate the efficacy of electrical stimulation by comparing network-mediated RGC responses in normal and degenerate retinas using a N-methyl-N-nitrosourea (MNU)-induced non-human primate (NHPs) retinitis pigmentosa (RP) model. Adult cynomolgus monkeys were used for normal and outer retinal degeneration (RD) induced by MNU. The network-mediated RGC responses were recorded from the peripheral retina mounted on an 8 × 8 multielectrode array (MEA). The amplitude and duration of biphasic current pulses were modulated from 1 to 50 μA and 500 to 4000 μs, respectively. The threshold charge density for eliciting a network-mediated RGC response was higher in the RD monkeys than in the normal monkeys (1.47 ± 0.13 mC/cm2 vs. 1.06 ± 0.09 mC/cm2, p < 0.05) at a 500 μs pulse duration. The monkeys required a higher charge density than rodents among the RD models (monkeys; 1.47 ± 0.13 mC/cm2, mouse; 1.04 ± 0.09 mC/cm2, and rat; 1.16 ± 0.16 mC/cm2, p < 0.01). Increasing the pulse amplitude and pulse duration elicited more RGC spikes in the normal primate retinas. However, only pulse amplitude variation elicited more RGC spikes in degenerate primate retinas. Therefore, the pulse strategy for primate RD retinas should be optimized, eventually contributing to retinal prosthetics. Given that RD NHP RGCs are not sensitive to pulse duration, using shorter pulses may potentially be a more charge-effective approach for retinal prosthetics.

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Electrical response of retinal ganglion cells in an N-methyl-N-nitrosourea-induced retinal degeneration porcine model

Cited by 6 publications

References 43 publications

Stage-Dependent Changes of Visual Function and Electrical Response of the Retina in the rd10 Mouse Model

Stage-Dependent Changes of Visual Function and Electrical Response of the Retina in the rd10 Mouse Model

Correlated Activity in the Degenerate Retina Inhibits Focal Response to Electrical Stimulation

The Variation of Electrical Pulse Duration Elicits Reliable Network-Mediated Responses of Retinal Ganglion Cells in Normal, Not in Degenerate Primate Retinas

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