Intrinsically Photosensitive Retinal Ganglion Cells of the Human Retina

Abstract

Light profoundly affects our mental and physical health. In particular, light, when not delivered at the appropriate time, may have detrimental effects. In mammals, light is perceived not only by rods and cones but also by a subset of retinal ganglion cells that express the photopigment melanopsin that renders them intrinsically photosensitive (ipRGCs). ipRGCs participate in contrast detection and play critical roles in non-image-forming vision, a set of light responses that include circadian entrainment, pupillary light reflex (PLR), and the modulation of sleep/alertness, and mood. ipRGCs are also found in the human retina, and their response to light has been characterized indirectly through the suppression of nocturnal melatonin and PLR. However, until recently, human ipRGCs had rarely been investigated directly. This gap is progressively being filled as, over the last years, an increasing number of studies provided descriptions of their morphology, responses to light, and gene expression. Here, I review the progress in our knowledge of human ipRGCs, in particular, the different morphological and functional subtypes described so far and how they match the murine subtypes. I also highlight questions that remain to be addressed. Investigating ipRGCs is critical as these few cells play a major role in our well-being. Additionally, as ipRGCs display increased vulnerability or resilience to certain disorders compared to conventional RGCs, a deeper knowledge of their function could help identify therapeutic approaches or develop diagnostic tools. Overall, a better understanding of how light is perceived by the human eye will help deliver precise light usage recommendations and implement light-based therapeutic interventions to improve cognitive performance, mood, and life quality.

Keywords: intrinsically photosensitive ganglion cell; melanopsin (OPN4); non-visual responses to light; retina; retinal ganglion cell.

Figure 1

ipRGCs in the mouse and human retinas. (Upper panels) Relative spectral sensitivity of the rods, cones, and ipRGCs. (Middle panels) Diagram of murine and human retinas displaying the differences regarding the morphological subtypes of ipRGCs, their IPL dendritic stratification, and outer retina photoreceptors. (Lower panels) Morphological comparison between subtypes and species. Soma and dendritic tree measurements are rounded to the closest integer. Mouse data are from Sondereker et al. (21) that compiled them from literature. Human data are from Esquiva et al. (22), Hannibal et al. (23), Liao et al. (24), and Nasir-Ahmad et al. (25). GM1, gigantic M1; dM1, displaced M1; dGM1, displaced gigantic M1; PRL, photoreceptors layer; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner plexiform layer; IPL, inner plexiform layer; GCL, ganglion cells layer.

Figure 2

Human ipRGCs morphological subtypes. (A–C) Reconstruction and pseudocoloring of ipRGCs from three separate human retina volumes based on melanopsin immunoreactivity. Upper left subpanels illustrate the different ipRGCs detected in the volumes, their relative size, and arrangement toward each other. In the other subpanels, each ipRGC is then identified and represented separately to appreciate the details of their dendritic arborization. dM1, displaced M1; GM1, gigantic M1; dGM1, displaced gigantic M1. Scale bars: A, 100 μm; B, 80 μm; C, 50 μm [Figure adapted from Hannibal et al. (23); courtesy of Dr. J. Hannibal and Journal of Comparative Neurology].

Figure 3

Human ipRGCs integrate extrinsic signals. Individual examples of type 1, 2, and 3 ipRGCs' responses to increasing irradiance light pulses (gray bars, 30 s, 470 nm; from bottom to top, irradiance is 2.9 × 10¹¹, 3.5 × 10¹², 2 × 10¹³, and 2 × 10¹⁴ photons/cm² per second). Red traces represent the responses of pharmacologically isolated ipRGCs, which reflect their intrinsic photosensitivity. In contrast, black traces report the responses from the same cells in the absence of synaptic blockers and thus integrating input from outer retina photoreceptors. Time course, sensitivity, and intrinsic properties of the response differ between the ipRGC subtypes. The contribution from rods/cones to the overall ipRGC responses to light also seems to be subtype-specific. Interestingly, ipRGC subtypes may receive different inputs from photoreceptors. Of note, in human, morphological and functional ipRGC subtypes are not yet fully consolidated; here, ipRGC subtypes are labeled as in the original study from which this figure is adapted (55).