Multiple vulnerability of photoreceptors to mesopic ambient light in the P23H transgenic rat

Abstract

The P23H transgenic rat was engineered to mimic a human form of retinal degeneration caused by a mutation in rhodopsin. We have tested whether the P23H transgene influences the vulnerability of photoreceptors to modest variations in ambient light, well within the physiological range. P23H-3 (P23H line 3) and control Sprague-Dawley (SD) rats were raised in cyclic light (12 h light, 12 h dark), with the light phase set at either 5 lx ('scotopic-reared') or 40-60 lx ('mesopic-reared'). Mesopic rearing reduced the length of outer segments (OSs) in both SD and P23H-3 strains, but the shortening was more marked in the P23H-3 strain. Mesopic rearing was associated with thinning of the ONL, again more prominently in the P23H-3. Correspondingly, mesopic rearing increased the rate of photoreceptor death (assessed by TUNEL labelling), the increase occurring during early postnatal life. Mesopic rearing upregulated FGF-2 (basic fibroblast growth factor) levels in photoreceptors and glial fibrillary acidic protein (GFAP) in Müller cells in both SD and P23H-3 strains; again the changes were more marked in the P23H-3. Finally, mesopic rearing decreased the amplitude of the a-wave of the ERG in both strains; again the effect was greater in the P23H-3 strain. The ERG decline induced in both strains by mesopic-rearing can be explained by a reduction of functional OS membrane, due to a combination of photoreceptor death and OS shortening. The P23H-3 transgene makes photoreceptors abnormally vulnerable to modest levels of ambient light, their vulnerability being evident in multiple ways. In humans suffering photoreceptor degeneration from comparable genetic causes, light restriction may preserve the number and the function of photoreceptors.