The rod and cone cells of the mammalian retina are the principal photoreceptors for image forming vision. They transmit information via a chain of intermediate cells to the retinal ganglion cells, which in turn send signals from the retina to the brain. Loss of photoreceptor cells, as happens in a number of human diseases, leads to irreversible blindness. It has been shown that expression of a light sensitive bacterial protein, channelrhodopsin-2, in the surviving non-photoreceptor neurons, can restore neuronal responsiveness and simple visual abilities in a mouse model (rd⁄rd) of photoreceptor degeneration. Here, we used a viral vector to express in retinal ganglion cells a native mammalian protein, melanopsin, which is also photosensitive but uses a different signaling mechanism. Whole-cell patch-clamp recording showed photoresponses in these cells, even after degeneration of the photoreceptors and additional pharmacological or Cd++ block of synaptic function. Interestingly, similar responses were observed across a wide variety of the retina's diverse types of ganglion cell. The newly melanopsin-expressing ganglion cells provided an enhancement of visual function in rd⁄rd mice: the pupillary light reflex (PLR) returned almost to normal; the mice showed behavioral avoidance of light in an open field test; and they could discriminate a light stimulus from a dark one in a two-choice visual discrimination alley. Recovery of the PLR was stable for at least 11 months. For therapy in human photodegenerations, channelrhodopsin-2 and melanopsin have different advantages and disadvantages; both proteins (or modifications of them) should probably be candidates.
PNAS, 2008, in the week of Sept 29.
