Blockade of Retinal Oscillations by Benzodiazepines Improves Efficiency of Electrical Stimulation in the Mouse Model of RP, <i>rd10</i>

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.

Section: Discussionmentioning

confidence: 99%

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

Ahn

Cha

Choi

et al. 2022

“…Past work has largely converged on a model where a gap junction coupled excitatory network, gives rise to oscillatory spontaneous activity in the rd10 retina ( Euler and Schubert, 2015 ; Trenholm and Awatramani, 2015 , for review) although, studies indicated that inhibition plays a role in modulating this spontaneous activity ( Margolis and Detwiler, 2011 ; Biswas et al, 2014 ; Gehlen et al, 2020 ). To examine how inhibition modulates or synchronizes spontaneous activity in response to stimulation, we repeated these experiments during inhibitory neurotransmitter block.…”

Section: Resultsmentioning

confidence: 99%

“…Spontaneous activity typically manifests as rhythmic bursting or oscillatory activity. Previous studies, most commonly in the rd1 or rd10 ( Chang et al, 2002 ) mouse models, have shown significant variability in the characteristics of spontaneous activity, such as the dominant frequency, as well as the underlying changes that could mediate this aberrant activity ( Margolis and Detwiler, 2011 ; Biswas et al, 2014 ; Gehlen et al, 2020 ). Putative mechanisms for spontaneous activity can be broadly divided into inner and outer retina mechanisms, which are not mutually exclusive [for review see, Euler and Schubert (2015) and Trenholm and Awatramani (2015) ].…”

Section: Introductionmentioning

confidence: 99%

Differences in the spatial fidelity of evoked and spontaneous signals in the degenerating retina

Carleton

Oesch²

2022

Vision restoration strategies aim to reestablish vision by replacing the function of lost photoreceptors with optoelectronic hardware or through gene therapy. One complication to these approaches is that retinal circuitry undergoes remodeling after photoreceptor loss. Circuit remodeling following perturbation is ubiquitous in the nervous system and understanding these changes is crucial for treating neurodegeneration. Spontaneous oscillations that arise during retinal degeneration have been well-studied, however, other changes in the spatiotemporal processing of evoked and spontaneous activity have received less attention. Here we use subretinal electrical stimulation to measure the spatial and temporal spread of both spontaneous and evoked activity during retinal degeneration. We found that electrical stimulation synchronizes spontaneous oscillatory activity, over space and through time, thus leading to increased correlations in ganglion cell activity. Intriguingly, we found that spatial selectivity was maintained in rd10 retina for evoked responses, with spatial receptive fields comparable to wt retina. These findings indicate that different biophysical mechanisms are involved in mediating feed forward excitation, and the lateral spread of spontaneous activity in the rd10 retina, lending support toward the possibility of high-resolution vision restoration.

“…Ongoing ganglion cell activity could, therefore, provide input to V1 even without visual input or functional photoreceptors. Indeed, because of photoreceptor loss, the remaining retina develops aberrant oscillatory activity in mouse models of retinitis pigmentosa ( rd1 and rd10 ) (Margolis et al, 2008 ; Biswas et al, 2014 ; Goo et al, 2016 ; Ivanova et al, 2016 ; Gehlen et al, 2020 ; Ahn et al, 2022 ) and hyperactivity in retinal ganglion cells (Margolis and Detwiler, 2011 ; Stasheff et al, 2011 ; Telias et al, 2019 ; Ahn et al, 2022 ). This aberrant retinal activity develops with the onset of retinal degeneration and is reported for our age group III and beyond, up until 12 months (Stasheff et al, 2011 ; Biswas et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Electrophysiological properties of layer 2/3 pyramidal neurons in the primary visual cortex of a retinitis pigmentosa mouse model (rd10)

Halfmann,

Rüland,

Müller

et al. 2023

Self Cite

Retinal degeneration is one of the main causes of visual impairment and blindness. One group of retinal degenerative diseases, leading to the loss of photoreceptors, is collectively termed retinitis pigmentosa. In this group of diseases, the remaining retina is largely spared from initial cell death making retinal ganglion cells an interesting target for vision restoration methods. However, it is unknown how downstream brain areas, in particular the visual cortex, are affected by the progression of blindness. Visual deprivation studies have shown dramatic changes in the electrophysiological properties of visual cortex neurons, but changes on a cellular level in retinitis pigmentosa have not been investigated yet. Therefore, we used the rd10 mouse model to perform patch-clamp recordings of pyramidal neurons in layer 2/3 of the primary visual cortex to screen for potential changes in electrophysiological properties resulting from retinal degeneration. Compared to wild-type C57BL/6 mice, we only found an increase in intrinsic excitability around the time point of maximal retinal degeneration. In addition, we saw an increase in the current amplitude of spontaneous putative inhibitory events after a longer progression of retinal degeneration. However, we did not observe a long-lasting shift in excitability after prolonged retinal degeneration. Together, our results provide evidence of an intact visual cortex with promising potential for future therapeutic strategies to restore vision.