Restoration of visual function in retinal degeneration mice by ectopic expression of melanopsin

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-10, Vol.105 (41), p.16009-16014
• Main Authors: Lin, Bin, Koizumi, Amane, Tanaka, Nobushige, Panda, Satchidananda, Masland, Richard H
• Format: Article
• Language: English
• Subjects: Alleys; Amacrine cells; Animals; Biological Sciences; Cells; Ganglia; Gene expression; Light; Mice; Neurons; Photic Stimulation; Photoreceptor Cells, Vertebrate; Photoreceptors; Pigments; Proteins; Retina; Retinal degeneration; Retinal Degeneration - therapy; Retinal Ganglion Cells - metabolism; Rod Opsins - administration & dosage; Rod Opsins - genetics; Rod Opsins - therapeutic use; Rodents; Transduction, Genetic; Vision, Ocular - genetics; Visual discrimination
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0806114105

The rod and cone cells of the mammalian retina are the principal photoreceptors for image-forming vision. They transmit information by means of 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. In a mouse model (rd/rd) of photoreceptor degeneration, we used a viral vector to express in a large number of retinal ganglion cells the light sensitive protein melanopsin, normally present in only a specialized subset of the cells. Whole-cell patch-clamp recording showed photoresponses in these cells even after degeneration of the photoreceptors and additional pharmacological or Cd²⁺ block of synaptic function. Interestingly, similar responses were observed across a wide variety of diverse types of ganglion cell of the retina. 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. It has recently been shown that ectopic retinal expression of a light sensitive bacterial protein, channelrhodopsin-2, can restore neuronal responsiveness and simple visual abilities in rd/rd mice. For therapy in human photodegenerations, channelrhodopsin-2 and melanopsin have different advantages and disadvantages; both proteins (or modifications of them) should be candidates.