Inner retinal photoreception independent of the visual retinoid cycle - PubMed (original) (raw)

Inner retinal photoreception independent of the visual retinoid cycle

Daniel C Tu et al. Proc Natl Acad Sci U S A. 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.

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Conflict of interest statement

Conflict of interest statement: No conflicts declared.

Figures

Fig. 1.

Fig. 1.

PLRs. Irradiance–response relations for PLRs of rdta, rpe65_−/−, rpe65_−/−;rdta (a) and rd/rd, lrat_−/−, lrat_−/−;rd/rd (b) mice stimulated by 470-nm narrow bandpass filtered light (n = 6–9, mean ± SEM). Pupillary constriction (c_–_n) was stimulated by 470 nm light (3.98 × 1014 photons·sec−1·cm−2). An rdta pupil before (c) and after (d) 30 s of light exposure is shown. An rpe65_−/− pupil before (e) and after (f) 30 s of light exposure is shown. An rpe65_−/−; rdta pupil before (g) and after (h) 30 s of light exposure is shown. An rd/rd pupil before (i) and after (j) 30 s of light exposure is shown. An lrat_−/− pupil before (k) and after (l) 30 s of light exposure is shown. An lrat_−/−; rd/rd pupil before (m) and after (n) 30 s of light exposure is shown.

Fig. 2.

Fig. 2.

_All_-_trans_-retinylamine inhibits outer but not inner retinal photosensitivity. Irradiance–response relations for PLRs of C57BL/6 (a), _opn4_−/− (b), and rd/rd (c) mice before (control) and 24 h after (Ret-NH2) oral gavage of 1 mg Ret-NH2. n = 3, 3, and 5 for C57BL/6, _opn4_−/−, and rd/rd, respectively; mean ± SEM.

Fig. 3.

Fig. 3.

9-_cis_-retinal partially rescues PLR sensitivity of rpe65_−/−;rdta mice. Irradiance–response relations for PLRs of rd/rd (a) and rpe65_−/−;rdta (b) mice before and 24 h after oral gavage of 1-mg 9-cis_-retinal. n = 5 for rpe65_−/−;rdta, n = 6 for rd/rd; mean ± SEM; asterisks indicate significance P < 0.05 by Wilcoxon ranked sums test.

Fig. 4.

Fig. 4.

ipRGC light responses of _rpe65_−/− and _lrat_−/− mice. Light-induced action potentials recorded from individual ipRGCs from C57BL/6 (a), _rpe65_−/− (b), and _lrat_−/− (c) P8 mouse retinas via multielectrode array. Timing of light stimulus (60 s, 480 nm, 4.11 × 1013 photons·sec−1·cm−2) is indicated by step in horizontal line below recordings. Zero voltage is indicated by dashed line. Cumulative average time course of type I ipRGC activity from C57BL/6 (d), _rpe65_−/− (e), and _lrat_−/− (f) retinas in response to subsaturating and saturating light stimulation (60 s, 480 nm light pulse is indicated by step in horizontal line below histograms). n = 27, 45, and 43 cells for d, e, and f, respectively; mean, 1-s bins.

Fig. 5.

Fig. 5.

Irradiance–response relations of _rpe65_−/− and _lrat_−/− ipRGCs. Irradiance–response relationships for P8 type I (a), II (b), and III (c) ipRGCs from C57BL/6, _rpe65_−/−, and _lrat_−/− mice. For C57BL/6, _rpe65_−/−, and _lrat_−/−, respectively: n = 27, 45, and 43 cells in a, n = 6, 3, and 8 cells in b, and n = 4, 5, and 8 cells in c; mean ± SEM.

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