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Rod Loss Restores Sensitivity to the Melanopsin System

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Rod Loss Restores Sensitivity to the Melanopsin System Nonvisual light responses in the Rpe65 knockout mouse: Rod loss restores sensitivity to the melanopsin system Susan E. Doyle*†, Ana Maria Castrucci*‡, Maureen McCall§, Ignacio Provencio*, and Michael Menaker* *Department of Biology, University of Virginia, Charlottesville, VA 22904; ‡Graduate Program in Physiology, Institute of Bioscience, University of Sa˜o Paulo, 05508-900, Sa˜o Paulo, Brazil; and §Departments of Ophthalmology and Visual Sciences and Psychological and Brain Sciences, University of Louisville, Louisville, KY 40292 Edited by Joseph S. Takahashi, Northwestern University, Evanston, IL, and approved May 8, 2006 (received for review February 6, 2006) Intrinsically photosensitive retinal ganglion cells (ipRGCs) express- in a series of enzymatic reactions taking place in both photore- ing the photopigment melanopsin (OPN4), together with rods and ceptor outer segments and the adjacent RPE (retinal pigment cones, provide light information driving nonvisual light responses. epithelium), is reisomerized into the 11-cis form. This process, We examined nonvisual photoreception in mice lacking RPE65, a the retinoid or visual cycle, is critical for sustained photorecep- protein that is required for regeneration of visual chromophore in tion (for review, see ref. 15). Whether melanopsin shares com- rods and cones. Although Rpe65 knockouts retain a small degree ponents of the visual cycle is not known. of rod function, we show here that circadian phase shifting To determine whether melanopsin uses a pathway for chro- -responses in Rpe65؊/؊ mice are attenuated far beyond what has mophore regeneration that is similar to that of rods, we exam been reported for rodless͞coneless mice. Furthermore, the number ined circadian photoentrainment in mice with targeted disrup- of melanopsin-immunoreactive perikarya and the extent of den- tion of Rpe65 (16), a gene encoding the recently identified Ϫ Ϫ dritic arborizations were decreased in Rpe65 knockout mice com- retinoid isomerohydrolase (17–19). Rpe65 / mice lose all cone pared with controls. To assess the nature of the photoreceptive function and almost completely lack rod function (20, 21). At defect in Rpe65 null mice, we eliminated either rods or melanopsin high light intensities, a small electroretinographic signal can be -from Rpe65؊/؊ retinas by generating (i) Rpe65؊/؊ mice carrying a detected from insensitive rods functioning through a 9-cis transgene (rdta) that results in selective elimination of rods and (ii) retinaldehyde chromophore (16, 20, 22). Because circadian double knockout Rpe65؊/؊;Opn4؊/؊ mice. Surprisingly, rod loss in responses to light in rodless͞coneless mice are unattenuated Rpe65 knockout mice resulted in restoration of circadian photo- (23), we hypothesized that if melanopsin-containing ipRGCs Ϫ Ϫ sensitivity. Normal photoentrainment was lost in Rpe65؊/؊; recycled chromophore by using RPE65, then Rpe65 / mice -Opn4؊/؊ mice, and, instead, a diurnal phenotype was observed. would show loss of circadian photosensitivity. Reduced sensi Ϫ Ϫ Our findings demonstrate that RPE65 is not required for ipRGC tivity of the pupillary light reflex in Rpe65 / mice lacking rod function but reveal the existence of a mechanism whereby rods and cone function suggests that melanopsin is sensitive to RPE65 may influence the function of ipRGCs. loss (21, 24). Here, we report dramatically decreased circadian photosen- Ϫ Ϫ circadian ͉ entrainment ͉ chromophore ͉ isomerohydrolase sitivity accompanied by inner retinal remodeling in Rpe65 / mice. We characterize the photoreceptor input to the nonvisual Ϫ/Ϫ ntrainment of circadian rhythms, pupillary constriction, photic system of Rpe65 mice by generating mice lacking both RPE65 and rods (Rpe65Ϫ/Ϫ;rdta) or RPE65 and melanopsin Emasking of locomotor activity, and suppression of pineal Ϫ/Ϫ Ϫ/Ϫ melatonin are examples of ‘‘non-image-forming,’’ light- (Rpe65 ;Opn4 ). We demonstrate that ablation of rods dependent phenomena, so called because they persist in the rescues the circadian and morphological defects resulting from RPE65 loss, and we propose mechanisms by which visual absence of the photoreceptors that subserve vision, the retinal Ϫ/Ϫ rods and cones (1). In rodless͞coneless mice, these light re- photoreceptors might alter ipRGC function in the Rpe65 sponses depend on melanopsin (Opn4), an inner retinal opsin retina. that is localized to a small subset of intrinsically photosensitive Results retinal ganglion cells (ipRGCs) (2–6). Melanopsin-containing ipRGCs send projections to brain nuclei that are involved in Locomotor Activity Rhythms. To determine whether loss of RPE65 affects circadian photoreception, we examined circadian loco- circadian entrainment and the pupillary light reflex (4, 7, 8). In Ϫ/Ϫ ϩ/Ϫ ϩ/ϩ melanopsin knockout mice, ipRGCs lose their photosensitivity; motor activity rhythms in Rpe65 , Rpe65 , and Rpe65 mice under entrained and free-running conditions (Fig. 1 A–C). however, nonvisual photoresponses, although attenuated, are ͞ not lost (9, 10). Although these data indicate redundancy among All three genotypes entrained to a 12-h light 12-h dark (LD) cycle; however, the phase angle of activity onset in relation to the rods, cones, and ipRGCs, the specific role(s) of each of these Ϫ/Ϫ three photoreceptors and their possible interactions in nonvisual LD cycle was altered for Rpe65 mice compared with the two photoreception are not understood. control groups (Fig. 1D). Whereas control mice began their Heterologously expressed melanopsin forms a functional pho- topigment that signals through an invertebrate-like phosphoino- Conflict of interest statement: No conflicts declared. sitide phototransduction cascade (11–13). A retinaldehyde chro- This paper was submitted directly (Track II) to the PNAS office. mophore is necessary to achieve light responses, and although Abbreviations: ipRGC, intrinsically photosensitive retinal ganglion cell; LD, 12-h light͞12-h recent studies suggest that melanopsin may be a bistable pho- dark; DD, constant darkness; CT, circadian time; IPL, inner plexiform layer; TBS, Tris- topigment that is able to reisomerize chromophore within the buffered saline. opsin molecule (12–14), we do not yet have a full understanding See Commentary on page 10153. of chromophore regeneration in ipRGCs. In vertebrate rods, the †To whom correspondence should be addressed at: Department of Biology, University light-sensitive chromophore 11-cis-retinaldehyde is bound to of Virginia, Gilmer Hall, P.O. Box 403028, Charlottesville, VA 22904. E-mail: sed5c@ opsin apoprotein and is isomerized by light to all-trans- virginia.edu. retinaldehyde. The all-trans product is released by the opsin and, © 2006 by The National Academy of Sciences of the USA 10432–10437 ͉ PNAS ͉ July 5, 2006 ͉ vol. 103 ͉ no. 27 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0600934103 Downloaded by guest on September 29, 2021 SEE COMMENTARY Fig. 1. Locomotor activity rhythms in Rpe65 mice. (A–C) Representative running wheel records of WT (Rpe65ϩ/ϩ)(A), Rpe65 heterozygote (Rpe65ϩ/Ϫ) (B), and homozygous Rpe65 knockout (Rpe65Ϫ/Ϫ)(C) mice. Each horizontal line represents 24 h, with successive days plotted beneath each other. Activity Fig. 2. Phase shifting to light is reduced in Rpe65Ϫ/Ϫ mice. (A) Magnitude of ͞ was first recorded in a light dark cycle (lights on at 0500 h and off at 1700 h) phase delays produced by 15 min of 515-nm light at three different irradi- as indicated by open and filled bars at the top of each record. Animals were ances. Handling controls were removed from their cages at CT 16 and placed then transferred to DD (arrows) and given a 15-min light pulse (515 nm and 0.1 in the light-pulse apparatus exactly as with experimental animals except that ␮ W) at CT 16 (4 h after activity onset; filled circle). (D) Mean number of minutes no light pulse was given. (Inset) Mean phase shift to a 15-min light pulse Ϯ Ͻ ( SEM) by which activity onset preceded dark onset (ZT12). ***, P 0.001 applied at CT 23.5, which shifts locomotor activity in the opposite direction compared with controls, one-way ANOVA with post hoc Tukey’s honestly (advance shift). (B) Phase shifts to 15 min of 480-nm light at CT 16. Error bars significant difference test. indicate SEM. *, P Ͻ 0.05 compared with controls; **, P Ͻ 0.01 compared with controls, one-way ANOVA with post hoc Tukey’s honestly significant differ- ence test. ␮W values are per cm2. nightly bout of activity just before lights off (Rpe65ϩ/ϩ, 10.1 Ϯ 8.6 min before lights off; Rpe65ϩ/Ϫ, 15.6 Ϯ 16.0 min before lights off), activity onset in Rpe65Ϫ/Ϫ mice occurred significantly Rpe65ϩ/ϩ, 156 Ϯ 11 min; Rpe65ϩ/Ϫ, 135 Ϯ 14 min; Rpe65Ϫ/Ϫ, earlier (125 Ϯ 32 min before lights off; P ϭ 0.0003, ANOVA, 13 Ϯ 8 min; P ϭ 0.001, ANOVA, post hoc Tukey’s test). post hoc Tukey’s test). However, on the first day of constant However, as irradiance was increased to saturating levels (1–10 darkness (DD), the time of activity onset did not differ among ␮W͞cm2), the magnitude of phase shifts in Rpe65Ϫ/Ϫ mice also genotypes (Rpe65ϩ/ϩ, 16.1 Ϯ 0.1 h, n ϭ 6; Rpe65ϩ/Ϫ, 15.5 Ϯ 0.4 h, increased, indicating that the circadian system of Rpe65 knock- n ϭ 10; Rpe65Ϫ/Ϫ, 15.4 Ϯ 0.2 h, n ϭ 9; P ϭ 0.38, ANOVA), out mice is capable of responding to high-intensity light as well suggesting that the knockout animals were not entrained with an as entraining to repeated long-duration light signals (Fig. 2). In advanced phase angle but were exhibiting light-dependent pos- response to 10 ␮W͞cm2 light, mean phase shift for knockout itive masking of locomotor activity. Alpha, the length of the animals reached control levels (Fig. 2; at 515 nm, Rpe65ϩ/ϩ, NEUROSCIENCE activity phase, did not differ among genotypes (Rpe65ϩ/ϩ, 7.96 Ϯ 143 Ϯ 5 min; Rpe65Ϫ/Ϫ, 102 Ϯ 22 min; P ϭ 0.28, ANOVA; at 480 0.18 h; Rpe65ϩ/Ϫ, 8.16 Ϯ 0.38 h; Rpe65Ϫ/Ϫ, 8.50 Ϯ 0.18 h; P ϭ nm, Rpe65ϩ/ϩ, 128 Ϯ 5 min; Rpe65Ϫ/Ϫ, 122 Ϯ 13 min; P ϭ 0.85, 0.77, ANOVA).
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