Intrinsically photosensitive retinal ganglion cell
Intrinsically photosensitive retinal ganglion cells (ipRGCs), also called photosensitive retinal ganglion cells (pRGC), or melanopsin-containing retinal ganglion cells (mRGCs), are a type of neuron in the retina of the mammalian eye. The presence of an additional photoreceptor was first suspected in 1927 when mice lacking rods and cones still responded to changing light levels through pupil constriction;[1] this suggested that rods and cones are not the only light-sensitive tissue.[2] However, it was unclear whether this light sensitivity arose from an additional retinal photoreceptor or elsewhere in the body. Recent research has shown that these retinal ganglion cells, unlike other retinal ganglion cells, are intrinsically photosensitive due to the presence of melanopsin, a light-sensitive protein. Therefore, they constitute a third class of photoreceptors, in addition to rod and cone cells.[3]
Compared to the rods and cones, the ipRGCs respond more sluggishly and signal the presence of light over the long term.[5] They represent a very small subset (~1%) of the retinal ganglion cells.[6] Their functional roles are non-image-forming and fundamentally different from those of pattern vision; they provide a stable representation of ambient light intensity. They have at least three primary functions:
Photoreceptive ganglion cells have been isolated in humans, where, in addition to regulating the circadian rhythm, they have been shown to mediate a degree of light recognition in rodless, coneless subjects suffering with disorders of rod and cone photoreceptors.[9] Work by Farhan H. Zaidi and colleagues showed that photoreceptive ganglion cells may have some visual function in humans.
The photopigment of photoreceptive ganglion cells, melanopsin, is excited by light mainly in the blue portion of the visible spectrum (absorption peaks at ~480 nanometers[10]). The phototransduction mechanism in these cells is not fully understood, but seems likely to resemble that in invertebrate rhabdomeric photoreceptors. In addition to responding directly to light, these cells may receive excitatory and inhibitory influences from rods and cones by way of synaptic connections in the retina.
The axons from these ganglia innervate regions of the brain related to object recognition, including the superior colliculus and dorsal lateral geniculate nucleus.[8]
Discovery[edit]
In 1923, Clyde E. Keeler observed that the pupils in the eyes of blind mice he had accidentally bred still responded to light.[2] The ability of the rodless, coneless mice to retain a pupillary light reflex was suggestive of an additional photoreceptor cell.[11]
In the 1980s, research in rod- and cone-deficient rats showed regulation of dopamine in the retina, a known neuromodulator for light adaptation and photoentrainment.[3]
Research continued in 1991, when Russell G. Foster and colleagues, including Ignacio Provencio, showed that rods and cones were not necessary for photoentrainment, the visual drive of the circadian rhythm, nor for the regulation of melatonin secretion from the pineal gland, via rod- and cone-knockout mice.[20][11] Later work by Provencio and colleagues showed that this photoresponse was mediated by the photopigment melanopsin, present in the ganglion cell layer of the retina.[21]
The photoreceptors were identified in 2002 by Samer Hattar, David Berson and colleagues, where they were shown to be melanopsin expressing ganglion cells that possessed an intrinsic light response and projected to a number of brain areas involved in non-image-forming vision.[22][23]
In 2005, Panda, Melyan, Qiu, and colleagues demonstrated that the melanopsin photopigment was the phototransduction pigment in ganglion cells.[24][25] Dennis Dacey and colleagues showed in a species of Old World monkey that giant ganglion cells expressing melanopsin projected to the lateral geniculate nucleus (LGN).[26][6] Previously only projections to the midbrain (pre-tectal nucleus) and hypothalamus (supra-chiasmatic nuclei, SCN) had been shown. However, a visual role for the receptor was still unsuspected and unproven.
Research[edit]
Research in humans[edit]
Attempts were made to hunt down the receptor in humans, but humans posed special challenges and demanded a new model. Unlike in other animals, researchers could not ethically induce rod and cone loss either genetically or with chemicals so as to directly study the ganglion cells. For many years, only inferences could be drawn about the receptor in humans, though these were at times pertinent.
In 2007, Zaidi and colleagues published their work on rodless, coneless humans, showing that these people retain normal responses to nonvisual effects of light.[9][27] The identity of the non-rod, non-cone photoreceptor in humans was found to be a ganglion cell in the inner retina as shown previously in rodless, coneless models in some other mammals. The work was done using patients with rare diseases that wiped out classic rod and cone photoreceptor function but preserved ganglion cell function.[9][27] Despite having no rods or cones, the patients continued to exhibit circadian photoentrainment, circadian behavioural patterns, melatonin suppression, and pupil reactions, with peak spectral sensitivities to environmental and experimental light that match the melanopsin photopigment. Their brains could also associate vision with light of this frequency. Clinicians and scientists are now seeking to understand the new receptor's role in human diseases and blindness.
Intrinsically photosensitive RGCs have also been implicated in the exacerbation of headache by light during migraine attacks.[28]