Functional and structural modifications during retinal degeneration in the rd10 mouse

Abstract

Mouse models of retinal degeneration are useful tools to study therapeutic approaches for patients affected by hereditary retinal dystrophies. We have studied degeneration in the rd10 mice both by immunocytochemistry and TUNEL-labeling of retinal cells, and through electrophysiological recordings. The cell degeneration in the retina of rd10 mice produced appreciable morphological changes in rod and cone cells by P20. Retinal cell death is clearly observed in the central retina and it peaked at P25 when there were 800 TUNEL-positive cells per mm(2). In the central retina, only one row of photoreceptors remained in the outer nuclear layer by P40 and there was a remarkable deterioration of bipolar cell dendrites postsynaptic to photoreceptors. The axon terminals of bipolar cells also underwent atrophy and the inner retina was subject to further changes, including a reduction and disorganization of AII amacrine cell population. Glutamate sensitivity was tested in rod bipolar cells with the single cell patch-clamp technique in slice preparations, although at P60 no significant differences were observed with age-matched controls. Thus, we conclude that rod and cone degeneration in the rd10 mouse model is followed by deterioration of their postsynaptic cells and the cells in the inner retina. However, the functional preservation of receptors for photoreceptor transmission in bipolar cells may open new therapeutic possibilities.

An Intrinsic Neural Oscillator in the Degenerating Mouse Retina

“…This finding was difficult to predict because photoreceptors that usually keep these cells in a hyperpolarized state (through a signinverting action mediated by mGluR6 receptors) are lost during RD. A negative resting potential in ON bipolar cells indicates that the mGluR6 receptor cascade is either downregulated (Strettoi and Pignatelli, 2000;Puthussery and Taylor, 2010) (but see Barhoum et al, 2008) or desensitized (Awatramani and Slaughter, 2000;Berntson et al, 2004). These data are also consistent with chemical labeling studies that suggest permanent closure of the mGluR6-gated cationic channel (Marc et al, 2003).…”

Inhibition of ceramide biosynthesis preserves photoreceptor structure and function in a mouse model of retinitis pigmentosa

“…The finding that ceramide levels increase in the rd10 mouse in temporal association with the process of photoreceptor demise (22,23) provides biochemical evidence that this sphingolipid is involved in the neurodegenerative pathology of RP. This result is therefore in accordance with the knowledge derived from genetic studies that human autosomal recessive RP can be caused by lossof-function mutations in CERKL, an enzyme that lowers ceramide content by phosphorylation (15).…”

“…Recently, the retinal degeneration 10 (rd10) mouse, with a missense mutation in the β-subunit of the rod-specific phosphodiesterase gene (21), has been shown, through morphological and functional retinal analyses, to be a faithful model of typical human RP (22,23). In this mutant, photoreceptors begin to die from apoptosis during the third week of life, after the postnatal period of retinal maturation, and photoreceptor death peaks around postnatal day 24 (P24) (22,23). As in typical human RP, rods die first, whereas cones are lost subsequently.…”

Lysosomal membrane permeabilization and autophagy blockade contribute to photoreceptor cell death in a mouse model of retinitis pigmentosa

“…The rd10 mouse, which harbours a mutation in the rod-specific phosphodiesterase gene Pde6b, is a suitable model of human retinitis pigmentosa. 23,24 This mutation results in reduced enzymatic function leading to increased cGMP and rod cell death, peaking around postnatal day 25 (P25), with only residual vision remaining after P30. 24,25 Here we show that rd10 mice exhibit massive intracellular calcium accumulation and m-calpain (calpain-2) activation at early ages, before the peak of photoreceptor cell death, that correlate with the blockade of autophagic flux.…”

“…23,24 This mutation results in reduced enzymatic function leading to increased cGMP and rod cell death, peaking around postnatal day 25 (P25), with only residual vision remaining after P30. 24,25 Here we show that rd10 mice exhibit massive intracellular calcium accumulation and m-calpain (calpain-2) activation at early ages, before the peak of photoreceptor cell death, that correlate with the blockade of autophagic flux. Moreover, we demonstrate an increase in cathepsin B activity in the cytoplasm of rd10 photoreceptors that correlates with the activation of DNAse II-dependent cell death.…”