inTRO to ipRGCs ( Intrinsically Photosensitive Retinal Ganglion Cells)

Rods, cones, and…ipRGCs?

For almost a century and a half, it was thought that the mammalian retina had just two types of photoreceptors: rods and cones. That assumption was not proven to be false until studies in the late 1990s proved the existence of a third kind of mammalian photoreceptor that differed greatly from rods and cones. These new types of photoreceptors were retinal ganglion cells (RGCs) that were intrinsically photosensitive (ipRGCs)— or in other words, naturally sensitive to light.

Though the official evidence to determine that ipRGCs actually existed did not come until much later, this third class of photoreceptor had already been hypothesized in 1927, nearly seven decades earlier, by a graduate student named Clyde Keeler. During one of his studies, he examined the behavior of mice that lacked nearly all rod and cone function as a result of severe retinal degradation, which left them functionally blind. Keeler noticed that despite the lack of rods and cones, the mice still had a very strong and significant pupillary constriction in response to light, and he determined that this response must have been the result of some third photoreceptor in the retina. The lack of concrete evidence for a whole new photoreceptor at the time resulted in this pupillary response being explained away by other scientists. However, in 1999, Russell Foster and his team would revisit Keeler’s work armed with a new host of tools.

Foster et al. worked with mice, much like Keeler did, but in their case, the mice being observed were genetically engineered to not have any rods or cones. Yet regardless of their missing rods and cones, the rats still displayed strong pupillary light reflexes and were even able to shift their circadian rhythms with shifting light exposure schedules. With these studies complete, the presence of a third photoreceptor was almost confirmed, but some still weren’t convinced because nobody had found another light-sensitive molecule (opsin) in the mammalian retina yet.  

The discovery of melanopsin in the photosensitive skin cells of frogs occurred in 1998, and in the following four years studies determined that the very same opsin was being expressed in a small percent of RGCs in both mouse and human retinas. This discovery allowed scientists to easily mark ipRGCs and confirm their existence, which finally put to rest the debate of whether or not there was a third class of photoreceptor.

So they exist, but what do they do?

IpRGCs differ greatly from rods and cones when it comes to how they work. Their main function in the body is to signal the intensity of ambient light levels (irradiance) to the brain. These signals are largely used for non-image-forming visual reflexes that are subconscious, such as pupillary constriction, neuroendocrine regulation, and synchronizing daily circadian physiological rhythms to environmental light. This means that the way ipRGCs respond to light by themselves is also quite different from rods and cones.

As mentioned before, these photoreceptors use melanopsin as their photopigment. and that makes them more responsive to light at around 480nm (blue light). In the graph below, you can see that this wavelength is significantly different from the best wavelengths for stimulating rods and cones (panel b).

Although ipRGCs function as photoreceptors themselves, it was found that they additionally receive synaptic input from the circuits of rods and cones. This means that ipRGCs have both an intrinsic light response coming from melanopsin and an extrinsic one that is mediated by synaptic input from rods and cones. The light response caused by melanopsin is markedly different from that of rods and cones: ipRGCs have both an intrinsic and sluggish light response as well as an extrinsic, rod/cone driven, rapid photoresponse. There is an ongoing debate about the relative significance of this extrinsic synaptic input and the role rods and cones play in determining our circadian rhythms.

A recent case study:

In a recent research article by Mouland et al., their team assessed whether the effective light intensity registered by melanopsin (blue light ~480nm) was a more important determinant of circadian impacts than that of cones under realistic contrast scenarios. The ability to determine melanopsin’s contribution to circadian light responses comes from the evolution of a color science technique which is referred to with multiple names, such as receptor silent substitution or metamerism in colorimetry. Metamerism occurs when two colors appear to match under a specific lighting condition but have different underlying spectra. 

This technique allows for the stimulation of specific photoreceptor classes, like ipRGCs. Mouland and colleagues quantified the circadian impacts of different photoreceptors by recording electrophysiological activity from the suprachiasmatic nucleus (SCN) of anaesthetised mice while they were presented with movies. The movies were either high or low contrast and had varying irradiances specialized for the distinct photoreceptor classes. 

During the experiment, the energy response recorded from the SCN closely tracked with melanopsin-driven signaling across all conditions. In general, steps in melanopic irradiance were determined to be the most significant factor accounting for light-induced changes in SCN activity. The only cone-directed lighting patterns with significant impacts on SCN activity were low contrast movie conditions. Basically, this study suggests that cones do have an impact on the circadian signal going to the SCN in some conditions, but the influence of melanopsin on the circadian signal is far more consistent.

This blog post was written by Arcascope’s intern, Ali Abdalla. Thanks, Ali!

This post used Webvision as a major resource. Thanks to Dustin Graham and Kwoon Wong for the excellent review.