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

Abstract

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.

Piceid Octanoate Protects Retinal Cells against Oxidative Damage by Regulating the Sirtuin 1/Poly-ADP-Ribose Polymerase 1 Axis In Vitro and in rd10 Mice

“…Moreover, we explored the morphology and distribution of RGCs via immunostaining Brn-3a, a transcription factor highly specific for RGCs in the retina (Figure 9H,K). Regarding retina architecture during the degeneration process of rd10 mice, it has been described that RGCs do not show significant changes until nine months of age [68]. As expected, we found that PIC-OCT did not induce significant changes in RGCs at P28 compared with the untreated group (Figure 9H,K).…”

“…Notably, a 20% reduction in rod bipolar cells emerges between P45 and P105, and a 39% decrease in horizontal cells is observed between P45 and P270. Intriguingly, RGCs do not exhibit significant changes until the mice reach nine months of postnatal age [68,106]. Exploring the enduring impact of PIC-OCT on rd10 mice through an extended treatment could offer valuable insights, providing a robust confirmation of its effects on RGCs.…”

Cones and cone pathways remain functional in advanced retinal degeneration

“…The visual signals of the ganglion cells are surprisingly robust, exhibiting small decreases in receptive field size (Figures 7G and 7H) and sensitivity (Figures 7K and 7L) but relatively normal temporal integration (Figures 7I and 7J) and information rates (Figures 7E and 7F). Though ganglion-cell responses in rd10 mice eventually degrade and disappear, 42 our results indicate that most of the mechanisms of visual integration in the outer and inner plexiform layers are intact and continue to function for a prolonged period, providing the mouse-at least under photopic conditions-with substantial visual function.…”

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

“…To investigate the RGC response range to changing pulse amplitudes, we applied stimulus amplitudes ranging from 1 to 50 µA with a fixed pulse duration of 500 µs. Our previous study identified this stimulus range (from 1 to 50 µA with a fixed pulse duration of 500 µs) as the optimal parameter to induce RGC spiking in WT and RD mice [10]. In both the normal and RD monkeys, more RGC spikes were elicited with the increasing pulse amplitude.…”

“…Through the progressive disappearance of the photoreceptor, the remaining retinal neurons migrate and form an abnormal synaptic connection [7]. The degenerate retina induces changes in the electrophysiological properties of RGCs, such as the appearance of an abnormal oscillation of the local field potential [8], the correlated firing of spikes among RGCs [9], multiple responses to a single pulse of electrical stimulation [10], and a reduced consistency in electrically evoked network-mediated responses [11]. Thus, an understanding of the RD network is a prerequisite for developing a retinal prosthesis for the blind.…”