Retinal degeneration 10 (rd10) mice are a model of autosomal recessive Retinitis Pigmentosa (RP), identified by Chang et al. in 2002. These mice carry a spontaneous mutation of the rodphosphodiesterase (PDE) gene, leading to a rod degeneration that starts around P18. Later, cones are also lost. Because of photoreceptor degeneration does not overlap with retinal development, and light responses can be recorded for about a month after birth, rd10 mice mimic typical human RP more closely than the well-known rd1 mutants. Aim of this study is to provide a comprehensive analysis of the morphology and function of the rd10 mouse retina during the period of maximum photoreceptor degeneration, thus contributing useful data for exploiting this novel model to study RP.We analyze the morphology and survival of retinal cells in rd10 mice of various ages with quantitative immunocytochemistry and confocal microscopy; we also study retinal function with the electroretinogram (ERG), recorded between P18 and P30.We find that photoreceptor death (peaking around P25) is accompanied and followed by dendritic retraction in bipolar and horizontal cells, which eventually undergo secondary degeneration. ERG reveals alterations in the physiology of the inner retina as early as P18 (before any obvious morphological change of inner neurons) and yet consistently with a reduced band amplification by bipolar cells.Thus, changes in the rd10 retina are very similar to what previously found in rd1 mutants. However, an overall slower decay of retinal structure and function predict that rd10 mice might become excellent models for rescue approaches.Keywords retinitis pigmentosa; bipolar cell; horizontal cell; confocal microscopy; immunocytochemistry; ERG A very high number of genetic mutations affect the eye. Those occurring in photoreceptor or pigment epithelium -specific genes often cause retinal degenerations (RDs), a family of inherited dystrophies characterized by photoreceptor dysfunction and death.It is estimated that more than 15 million people worldwide have vision loss due to inherited forms of RD. These include patients suffering from retinitis pigmentosa (RP), a disease for which there is no cure yet (Chader, 2002 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptFor over 30 years, the retina of rodents has provided an invaluable tool to study the dynamics and mechanisms of inherited RD, as mouse photoreceptors undergo dystrophies caused by spontaneous DNA mutations, closely related to those of humans.Among the mouse models, the best characterized is the retinal degeneration 1 (rd1) mouse, first described decades ago as a rodless phenotype (reviewed in Farber et al., 1994). This animal carries a spontaneous mutation of the β-subunit of the rod-phosphodiesterase (PDE) gene, causing the massive death of rods in the first weeks of postnatal life. As in typical RP, cones eventually die as well (LaVail et al., 1997;Pierce, 2001). The fast degeneration of photoreceptors is an obvious limit to the employment of r...
Retinitis pigmentosa (RP) is a genetic disease causing progressive apoptotic death of photoreceptors and, ultimately, incurable blindness. Using the retinal degeneration 10 (rd10) mouse model of RP, we investigated the role of ceramide, a proapoptotic sphingolipid, in retinal degeneration. We also tested the possibility that photoreceptor loss can be slowed or blocked by interfering with the ceramide signaling pathway of apoptosis in vivo. Retinal ceramide levels increased in rd10 mice during the period of maximum photoreceptor death. Single intraocular injections of myriocin, a powerful inhibitor of serine palmitoyl-CoA transferase, the ratelimiting enzyme of ceramide biosynthesis, lowered retinal ceramide levels to normal values and rescued photoreceptors from apoptotic death. Noninvasive treatment was achieved using eye drops consisting of a suspension of solid lipid nanoparticles loaded with myriocin. Short-term noninvasive treatment lowered retinal ceramide in a manner similar to intraocular injections, indicating that nanoparticles functioned as a vector permitting transcorneal drug administration. Prolonged treatment (10-20 d) with solid lipid nanoparticles increased photoreceptor survival, preserved photoreceptor morphology, and extended the ability of the retina to respond to light as assessed by electroretinography. In conclusion, pharmacological targeting of ceramide biosynthesis slowed the progression of RP in a mouse model, and therefore may represent a therapeutic approach to treating this disease in humans. Transcorneal administration of drugs carried in solid lipid nanoparticles, as experimented in this study, may facilitate continuous, noninvasive treatment of patients with RP and other retinal pathologies.sphingolipid | apoptosis | electroretinography | morphology
Key points• The mouse retina has become a key model for research on the function and dysfunction of the early stages of vision, but its photoreceptors have proven difficult to access with whole-cell recording techniques.• We have optimized the mouse retinal slice preparation to the degree required for studying photoreceptors with a reasonably high yield.• We find that single photon processing in rods is considerably more efficient than previously thought, implying a more favourable transmission at the rod-rod bipolar cell synapse.• Cones were recorded much more frequently than their numeric proportion of ∼3% allowing us to obtain direct functional evidence suggestive of rod-cone coupling in the mouse.• This study opens the way for further investigations into mammalian photoreceptor function by exploiting the powerful molecular genetic approaches available in the mouse. AbstractResearch on photoreceptors has led to important insights into how light signals are detected and processed in the outer retina. Most information about photoreceptor function, however, comes from lower vertebrates. The large majority of mammalian studies are based on suction pipette recordings of outer segment currents, a technique that doesn't allow examination of phenomena occurring downstream of phototransduction. Only a small number of whole-cell recordings have been made, mainly in the macaque. Due to the growing importance of the mouse in vision research, we have optimized a retinal slice preparation that allows the reliable collection of perforated-patch recordings from light responding rods and cones. Unexpectedly, the frequency of cone recordings was much higher than their numeric proportion of ∼3%. This allowed us to obtain direct functional evidence suggestive of rod-cone coupling in the mouse. Moreover, rods had considerably larger single photon responses than previously published for mammals (3.44 mV, SD 1.37, n = 19 at 24 • C; 2.46 mV, SD 1.08, n = 10 at 36 • C), and a relatively high signal/noise ratio (6.4, SD 1.8 at 24• C; 6.8, SD 2.8 at 36• C). Both findings imply a more favourable transmission at the rod-rod bipolar cell synapse. Accordingly, relatively few photoisomerizations were sufficient to elicit a half-maximal response (6.7, SD 2.7, n = 5 at 24• C; 10.6, SD 1.7, n = 3 at 36 • C), leading to a narrow linear response range. Our study demonstrates new features of mammalian photoreceptors and opens the way for further investigations into photoreceptor function using retinas from mutant mouse models.
The mammalian retina contains an autonomous circadian clock system that controls many physiological functions within this tissue. Previous studies on young mice have reported that removal of the key circadian clock gene Bmal1 from the retina affects the circadian regulation of visual function, but does not affect photoreceptor viability. Because dysfunction in the circadian system is known to affect cell viability during aging in other systems, we compared the effect of Bmal1 removal from the retina on visual function, inner retinal structure, and photoreceptor viability in young (1 to 3 months) and aged (24 to 26 months) mice. We found that removal of Bmal1 from the retina significantly affects visual information processing in both rod and cone pathways, reduces the thickness of inner retinal nuclear and plexiform layers, accelerates the decline of visual functions during aging, and reduces the viability of cone photoreceptors. Our results thus suggest that circadian clock dysfunction, caused by genetic or other means, may contribute to the decline of visual function during development and aging.
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