Inner Retinal Photoreception Independent of the Visual Retinoid Cycle

Mice lacking the visual cycle enzymes RPE65 or lecithin-retinol acyl transferase (Lrat) have pupillary light responses (PLR) that are less sensitive than those of mice with outer retinal degeneration (rd/rd or rdta). Inner retinal photoresponses are mediated by melanopsinexpressing, intrinsically photosensitive retinal ganglion cells (ipRGCs), suggesting that the melanopsin-dependent photocycle utilizes RPE65 and Lrat. To test this hypothesis, we generated$rpe65^{-/-}$; rdta and$Irat^{-/-}$; rd/rd mutant mice. Unexpectedly, both$rpe65^{-/-}$; rdta and$Irat^{-/-}$; rd/rd mice demonstrate paradoxically increased PLR photosensitivity compared with mice mutant in visual cycle enzymes alone. Acute pharmacologic inhibition of the visual cycle of melanopsin-deficient mice with all-trans-retinylamine results in a near-total loss of PLR sensitivity, whereas treatment of rd/rd mice has no effect, demonstrating that the inner retina does not require the visual cycle. Treatment of$rpe65^{-/-}$; rdta with 9-cis-retinal partially restores PLR sensitivity. Photic sensitivity in P8$rpe65^{-/-}$and$Irat^{-/-}$ipRGCs is intact as measured by ex vivo multielectrode array recording. These results demonstrate that the melanopsin-dependent ipRGC photocycle is independent of the visual retinoid cycle.