Aberrant synaptic input to retinal ganglion cells varies with morphology in a mouse model of retinal degeneration

Abstract

Retinal degeneration describes a group of disorders which lead to progressive photoreceptor cell death, resulting in blindness. As this occurs, retinal ganglion cells (RGCs) begin to develop oscillatory physiological activity. Here, we studied the morphological and physiological properties of RGCs in rd1 mice, aged 30–60 days, to determine how this aberrant activity correlates with morphology. Patch-clamp recordings of excitatory and inhibitory currents were performed, then dendritic structures were visualized by infusion of fluorescent dye. Only RGCs with oscillatory activity were selected for further analysis. Oscillatory frequency and power were calculated using power spectral density analysis of recorded currents. Dendritic arbor stratification, total length, and area were measured from confocal microscope image stacks. These measurements were used to sort RGCs by cluster analysis using Ward’s method. This resulted in a total of 10 clusters, with monostratified and bistratified cells having 5 clusters each. Both populations exhibited correlations between arbor stratification and aberrant inhibitory input, while excitatory input did not vary with arbor distribution. These findings illustrate the relationship between aberrant activity and RGC morphology at early stages of retinal degeneration.

Aberrant activity in retinal degeneration impairs central visual processing and relies on Cx36-containing gap junctions

“…Recent studies, however, cast new light to our understanding by revealing that functional changes within surviving retina lead to the emergence of aberrant neuronal activity. In particular, we found that this aberrant activity lowers signal fidelity in RD, exacerbating the visual deficit (Yee et al, 2014). Selectively reducing this activity by blocking gap junctions increases sensitivity to signals from surviving photoreceptors, and enhances the responses to electrical stimulation of the surviving retina (Toychiev et al, 2013a).…”

Retinal remodeling in human retinitis pigmentosa

“…Yet despite some localized recording of degenerate retina indicating aberrant processing (Homma et al, 2009) and retinal output from GCs (Sekirnjak et al, 2011), as well as efforts to examine gene expression in early ectopic synaptogenesis (Michalakis et al, 2013), very few studies have examined how these changes impact the precise retinal circuitry and function of the neural retina in degenerative disease in any of the various cell classes, despite over a decade of work from labs studying retinal degeneration and remodeling. That said, substantial efforts are being made to examine gap junctional coupling is altered (Ivanova et al, 2015a, Ivanova et al, 2015b) as well as exploring how retinal processing pathways are undergoing changes as a result of degeneration (Yee et al, 2014, Ivanova et al, 2016). …”

Prosthetic vision: devices, patient outcomes and retinal research

“…A significant factor influencing stimulation efficacy is the state of degeneration in the diseased retina. The substantial anatomical reorganisation that takes place over the course of degeneration is accompanied by extensive physiological changes, which have been investigated in several different animal models . Compared with the healthy retina, ganglion cells of the rd1 and rd10 mouse retina exhibit an elevated level of spontaneous activity that increases with photoreceptor degeneration (Figure C) .…”

“…The substantial anatomical reorganisation that takes place over the course of degeneration is accompanied by extensive physiological changes, which have been investigated in several different animal models. 34,[136][137][138] Compared with the healthy retina, ganglion cells of the rd1 and rd10 mouse retina exhibit an elevated level of spontaneous activity that increases with photoreceptor degeneration ( Figure 5C). 34,136,139,140 A particularly striking feature of the degenerate retina in these animals is the presence of oscillatory 'waves' of ganglion cell activity that fire at either~5 Hz (rd10) or~10 Hz (rd1).…”