Mutations in the cellular retinaldehyde–binding protein (CRALBP, encoded by RLBP1) can lead to severe cone photoreceptor–mediated vision loss in patients. It is not known how CRALBP supports cone function or how altered CRALBP leads to cone dysfunction. Here, we determined that deletion of Rlbp1 in mice impairs the retinal visual cycle. Mice lacking CRALBP exhibited M-opsin mislocalization, M-cone loss, and impaired cone-driven visual behavior and light responses. Additionally, M-cone dark adaptation was largely suppressed in CRALBP-deficient animals. While rearing CRALBP-deficient mice in the dark prevented the deterioration of cone function, it did not rescue cone dark adaptation. Adeno-associated virus–mediated restoration of CRALBP expression specifically in Müller cells, but not retinal pigment epithelial (RPE) cells, rescued the retinal visual cycle and M-cone sensitivity in knockout mice. Our results identify Müller cell CRALBP as a key component of the retinal visual cycle and demonstrate that this pathway is important for maintaining normal cone–driven vision and accelerating cone dark adaptation.

Bright light vision requires rapid regeneration of the photosensitive chromophore in cone photoreceptors. This study demonstrates that such rapid regeneration is accomplished via a pathway that resides in retinal Müller glia, with the final step being performed in the cones themselves. Daytime vision is mediated by retinal cones, which, unlike rods, remain functional even in bright light and dark-adapt rapidly. These cone properties are enabled by rapid regeneration of their pigment. This in turn requires rapid chromophore recycling that may not be achieved by the canonical retinal pigment epithelium visual cycle. Recent biochemical studies have suggested the presence of a second, cone-specific visual cycle, although its physiological function remains to be established. We found that the Müller cells in the salamander neural retina promote cone-specific pigment regeneration and dark adaptation that are independent of the pigment epithelium. Without this pathway, dark adaptation of cones was slow and incomplete. Notably, the rates of cone pigment regeneration by the retina and pigment epithelium visual cycles were essentially identical, suggesting a possible common rate-limiting step. Finally, we also observed cone dark adaptation in the isolated mouse retina.