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PNAS 103 (27): 10426-10431

Copyright © 2006 by the National Academy of Sciences.

From the Cover

BIOLOGICAL SCIENCES / NEUROSCIENCE

Inner retinal photoreception independent of the visual retinoid cycle

Daniel C. Tu*, Leah A. Owens*, Lauren Anderson*, Marcin Golczak{dagger}, Susan E. Doyle{ddagger}, Maureen McCall§, Michael Menaker{ddagger}, Krzysztof Palczewski{dagger}, and Russell N. Van Gelder*,¶,||

Departments of *Ophthalmology and Visual Sciences and Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, MO 63110; {dagger}Department of Pharmacology, Case Western Reserve School of Medicine, Cleveland, OH 44106-4965; {ddagger}Department of Biology, University of Virginia, Charlottesville, VA 22904; §and Departments of Ophthalmology and Visual Sciences and Psychological and Brain Sciences, University of Louisville, Louisville, KY 40292

Edited by Jeremy Nathans, Johns Hopkins University School of Medicine, Baltimore, MD, and approved May 8, 2006

Received for publication February 3, 2006.

Abstract: Mice lacking the visual cycle enzymes RPE65 or lecithin-retinol acyl transferase (Lrat) have pupillary light responses (PLR) that are less sensitive than those of mice with outer retinal degeneration (rd/rd or rdta). Inner retinal photoresponses are mediated by melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs), suggesting that the melanopsin-dependent photocycle utilizes RPE65 and Lrat. To test this hypothesis, we generated rpe65–/–; rdta and lrat–/–; rd/rd mutant mice. Unexpectedly, both rpe65–/–; rdta and lrat–/–; rd/rd mice demonstrate paradoxically increased PLR photosensitivity compared with mice mutant in visual cycle enzymes alone. Acute pharmacologic inhibition of the visual cycle of melanopsin-deficient mice with all-trans-retinylamine results in a near-total loss of PLR sensitivity, whereas treatment of rd/rd mice has no effect, demonstrating that the inner retina does not require the visual cycle. Treatment of rpe65–/–; rdta with 9-cis-retinal partially restores PLR sensitivity. Photic sensitivity in P8 rpe65–/– and lrat–/– ipRGCs is intact as measured by ex vivo multielectrode array recording. These results demonstrate that the melanopsin-dependent ipRGC photocycle is independent of the visual retinoid cycle.

Key Words: melanopsin • pupillary light response • retinal degeneration • retinal ganglion cell • visual photocycle

Author contributions: D.C.T., S.E.D., M. Menaker, K.P., and R.N.V.G. designed research; D.C.T., L.A.O., L.A., M.G., S.E.D., M. McCall, and R.N.V.G. performed research; D.C.T., M.G., S.E.D., M. McCall, M. Menaker, K.P., and R.N.V.G. contributed new reagents/analytic tools; D.C.T., L.A.O., M. Menaker, K.P., and R.N.V.G. analyzed data; and D.C.T., S.E.D., M. Menaker, K.P., and R.N.V.G. wrote the paper.

Conflict of interest statement: No conflicts declared.

This paper was submitted directly (Track II) to the PNAS office.

See Commentary on page 10153.

||To whom correspondence should be addressed. E-mail: vangelder{at}vision.wustl.edu

© 2006 by The National Academy of Sciences of the USA

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