Ait-Hmyed Hakkari_2016_FASEB.J_30_3690

The circadian clock is thought to adjust retinal sensitivity to ambient light levels, yet the involvement of specific clock genes is poorly understood. We explored the potential role of the nuclear receptor subfamily 1, group D, member 1 (REV-ERBalpha; or NR1D1) in this respect. In light-evoked behavioral tests, compared with wild-type littermates, Rev-Erbalpha(-/-) mice showed enhanced negative masking at low light levels (0.1 lx). Rev-Erbalpha(-/-) mouse retinas displayed significantly higher numbers of intrinsically photosensitive retinal ganglion cells (ipRGCs; 62% more compared with wild-type) and more intense melanopsin immunostaining of individual ipRGCs. In agreement with a pivotal role for melanopsin, negative masking at low light intensities was abolished in Rev-Erbalpha(-/-) Opn4(-/-) (melanopsin gene) double-null mice. Rev-Erbalpha(-/-) mice showed shortened latencies of both a and b electroretinogram waves, modified scotopic and photopic b-wave and scotopic threshold responses, and increased pupillary constriction, all of which suggested increased light sensitivity. However, wild-type and Rev-Erbalpha(-/-) mice displayed no detectable differences by in vivo fundus imaging, retinal histology, or expression of cell type-specific markers for major retinal cell populations. We conclude that REV-ERBalpha plays a major role in retinal information processing, and we speculate that REV-ERBalpha and melanopsin set sensitivity levels of the rod-mediated ipRGC pathway to coordinate activity with ambient light.