Genetically encoded optical neuromodulators create an opportunity for circuit-specific intervention in neurological diseases. One of the diseases most amenable to this approach is retinal degeneration, where the loss of photoreceptors leads to complete blindness. To restore photosensitivity, we genetically targeted a light-activated cation channel, channelrhodopsin-2, to second-order neurons, ON bipolar cells, of degenerated retinas in vivo in the Pde6brd1 (also known as rd1) mouse model. In the absence of 'classical' photoreceptors, we found that ON bipolar cells that were engineered to be photosensitive induced light-evoked spiking activity in ganglion cells. The rescue of light sensitivity was selective to the ON circuits that would naturally respond to increases in brightness. Despite degeneration of the outer retina, our intervention restored transient responses and center-surround organization of ganglion cells. The resulting signals were relayed to the visual cortex and were sufficient for the animals to successfully perform optomotor behavioral tasks.
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We thank B.G. Scherf, S. Djaffer, Y. Shimada and F. Ronay for technical assistance, K. Deisseroth for kindly providing us with the pLECYT lentiviral vector, and A. Lüthi, S. Picaud, M. Fendt, M. Stadler and C. Herry for their suggestions or help with the behavioral experiments. This study was supported by Friedrich Miescher Institute funds, an US Office of Naval Research Naval International Cooperative Opportunities in Science and Technology Program grant, a Marie Curie Excellence Grant, a Human Frontier Science Program Young Investigator grant (B.R.), a Marie Curie Postdoctoral Fellowship (D.B. and T.A.M.), a National Center for Competence in Research in Genetics fellowship (V.B.) and a Human Frontier Science Program Fellowship (G.B.A.)
Pamela S Lagali, David Balya, Thomas A Münch and Botond Roska have applied for a patent on the use of light-sensitive genes (WO 2008/022772).
Constance L Cepko, Douglas S Kim and Harvard University are submitting a patent application for the use of the Grm6 regulatory elements described in this publication.
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