Progression of neuronal and synaptic remodeling in the rd10 mouse model of retinitis pigmentosa

Abstract

The Pde6b rd10 (rd10) mouse has a moderate rate of photoreceptor degeneration and serves as a valuable model for human autosomal recessive retinitis pigmentosa (RP). We evaluated the progression of neuronal remodeling of second-and third-order retinal cells and their synaptic terminals in retinas from Pde6b rd10 (rd10)mice at varying stages of degeneration ranging from postnatal day 30 (P30) to postnatal month 9.5 (PNM9.5) using immunolabeling for well-known cell-and synapse-specific markers. Following photoreceptor loss, changes occurred progressively from outer to inner retina. Horizontal cells and rod and cone bipolar cells underwent morphological remodeling that included loss of dendrites, cell body migration, and the sprouting of ectopic processes. Gliosis, characterized by translocation of Müller cell bodies to the outer retina and thickening of their processes, was evident by P30 and became more pronounced as degeneration progressed. Following rod degeneration, continued expression of VGluT1 in the outer retina was associated with survival and expression of synaptic proteins by nearby secondorder neurons. Rod bipolar cell terminals showed a progressive reduction in size and ectopic bipolar cell processes extended into the inner nuclear layer and ganglion cell layer by PNM3.5. Putative ectopic conventional synapses, likely arising from amacrine cells, were present in the inner nuclear layer by PNM9.5. Despite these changes, the laminar organization of bipolar and amacrine cells and the ON-OFF organization in the inner plexiform layer was largely preserved. Surviving cone and bipolar cell terminals continued to express the appropriate cell-specific presynaptic proteins needed for synaptic function up to PNM9.5.

Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration

“…The increased expression of antioxidant genes in rd10 mice as degeneration progresses has been reported earlier (46) and was interpreted as a response to stress. The stress is likely associated with the death of cells in the INL secondary to the devastating PRC death in the ONL (40)(41)(42). INL death was confirmed by TUNEL assay (Fig.…”

“…3J) in rd10+PTZ mice than in rd10-non mice. Following PRC degeneration in rd10 mice, postsynaptic inner nuclear layer (INL) deterioration (rod bipolar and horizontal cell death) ensues (40)(41)(42). We asked whether (+)-PTZ treatment attenuated INL cell death in rd10 mice by evaluating TUNEL + cells along the horizontal retinal meridian because the degeneration follows a central-peripheral gradient (40).…”

Viral-mediated RdCVF and RdCVFL expression protects cone and rod photoreceptors in retinal degeneration

“…Here, we describe experiments that study the bifunctional nature of the Nxnl1 gene by evaluating the effects of expression of the 2 RdCVF isoforms RdCVF and RdCVFL via gene transfer in the rd10 and P23H mouse models of rod-cone dystrophy. The rd10 mouse is a well-characterized model of retinal degeneration resulting from a mutation in the β subunit of PDE6, the rod-specific cyclic GMP phosphodiesterase (15,16). rd10 retinal degeneration is slower than the rate of degeneration in the most widely studied model of recessive retinal degeneration, the rd1 mouse, which loses the majority of photoreceptors between P15 and P20.…”

Dark-Rearing the rd10 Mouse: Implications for Therapy

“…Immunolabeling of retinal cryosections was carried out according to previously described protocols (Sherry et al 2006; Phillips et al 2010). Antibodies used were rabbit PKCα (1/1000, Sigma, St. Louis, MO), rabbit VAMP-2 (1/500, ab3347 Abcam, MA), rabbit synapsin-1 (1/500, ab8), all raised in rabbit and detected using alexafluor-labeled secondary anti-rabbit antibodies (1/500, Molecular Probes, OR).…”