Role of melanopsin in photic responses In 1998, Provencio discovered
melanopsin as a new
opsin in the photosensitive skin melanophores of the
African clawed frog. In 2000, he showed that melanopsin is also present in
mouse,
rhesus macaques, and
humans, where it is only present in the eye. The unique inner retinal localization of melanopsin indicated that melanopsin was not involved in image formation. Later, he demonstrated that the melanopsin pigment might be involved in
entrainment of a
circadian oscillator to light cycles in mammals. He found that blind mice without classical photoreceptor cells (
rods and
cones) still had eye-mediated responses to light. Mice with the melanopsin gene
knocked out but with functional rods and cones were also able to entrain. However, when melanopsin was knocked out in blind mice without rods and cones, they exhibited "complete loss of
photoentrainment of the circadian oscillator, pupillary light responses, photic suppression of arylalkylamine-N-acetyltransferase transcript, and acute suppression of locomotor activity by light." The Opn4 -/- mice showed similar circadian behaviors as the normal mice: they entrained to light/dark cycles and free-ran under constant darkness in a way expected from the normal mice. This resulted in lowered responsiveness to light/dark cycles; a similar characteristic was observed in gene-knockout mutants lacking rods, cones or melanopsin. Furthermore, light-induced negative masking, mediated by rods, cones and/or melanopsin cells, was missing in the mice lacking melanopsin cells. Since
retinal ganglion cells that express melanopsin have also been found in humans, these studies suggest that blind humans who still retain functional melanopsin cells are those who are able to entrain to daily light cycles. These studies also show that blind patients who cannot entrain and lack melanopsin cells have a significantly greater risk of suffering from
circadian rhythm sleep disorders. While
enucleation of blind patients and babies was a common practice for cosmetic or analgesic reasons, doctors now must make a more cautious decision on whether to enucleate blind patients, especially infants, because they may still have functioning photosensitive retinal ganglion cells that express melanopsin. In addition, there are now studies attempting to optimize
light therapy for those with circadian rhythm sleep disorders that specifically try to stimulate melanopsin cells in blind patients.
Recent studies Provencio's research team has found that in albino mice, the amount of melanopsin protein in various retinal cells varies based on the environmental light conditions. In constant light conditions, melanopsin cell number did not increase. To further define the functions of RPE65, Provencio took Rpe65(-/-) mice and also eliminated rods. The technique used for this was insertion of the rdta
transgene, which selectively kills rods. They found that circadian
photosensitivity returned in these mice without RPE65 protein and without rods, versus mice without RPE65 protein that still had rods. Provencio also took Rpe65(-/-) mice and crossed them with
melanopsin knockout mice (Opn4(-/-)). This created double RPE and melanopsin knockout mice, which resulted in abnormal photoentrainment and
diurnal behavior. From these results, Provencio concluded that RPE65 is not necessary for the function of ipRGCs. However, because of the interesting restoration of circadian photosensitivity in rodless, RPE-less mice, there seems to be a mechanism by which rods can influence ipRGCs. ==See also==