title: Light-activated channels targeted to ON bipolar cells restore visual function in retinal degeneration.
abstract: 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 Pde6b(rd1) (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.
authors.affiliation: Neural Circuit Laboratories, Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Lagali
authors.forename: David
authors.initials: D
authors.lastname: Balya
authors.forename: Gautam B
authors.initials: GB
authors.lastname: Awatramani
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Münch
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Kim
authors.forename: Volker
authors.initials: V
authors.lastname: Busskamp
authors.forename: Constance L
authors.initials: CL
authors.lastname: Cepko
authors.forename: Botond
authors.initials: B
authors.lastname: Roska
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D018274:Electroporation / Q000379:methods; D005074:Evoked Potentials, Visual / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000235:genetics; D008027:Light; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology / Q000528:radiation effects; D018408:Patch-Clamp Techniques; D010775:Photic Stimulation / Q000379:methods; D010879:Piperazines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051245:Retinal Bipolar Cells / Q000502:physiology* / Q000528:radiation effects; D012162:Retinal Degeneration / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D012165:Retinal Ganglion Cells / Q000502:physiology; D012243:Rhodopsin / Q000502:physiology*; D013997:Time Factors; D014785:Vision, Ocular / Q000502:physiology* / Q000528:radiation effects; D014795:Visual Pathways / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects
chemical_list: D018691:Excitatory Amino Acid Antagonists; D008164:Luminescent Proteins; D010879:Piperazines; D011810:Quinoxalines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D012243:Rhodopsin; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid