A small percentage of mammalian retinal ganglion cells express the photopigment melanopsin and are capable of driving phototransduction independently of rods and cones [1–5]. Collectively termed intrinsically photosensitive retinal ganglion cells (ipRGCs), these specialized cells integrate their intrinsic melanopsin-mediated photoresponses with extrinsic signals derived from rods and cones to mediate all light-dependent, nonimage-forming behaviours in mammals [6,7]. Preliminary evidence suggests that they also have a role in visual perception [8,9,10▪▪]. The decade since their identification in 2002 as an independent photoreceptor has witnessed an explosion of investigative studies in related fields of molecular biology, cellular anatomy, chronobiology, neurobiology and visual science, to name a few. It is beyond the scope of this work to discuss details of the intrinsic phototransduction cascade, photopigment regeneration, retinal circuitry and electrophysiology of intrinsic photoresponses, but more information can be found in several excellent articles and reviews [11–15,16▪▪]. Herein, we recapitulate current concepts related to the morphology, central connections and behavioural functions of ipRGCs and highlight recent studies related to the clinical implications of ipRGCs.
SUBTYPES OF INTRINSICALLY PHOTOSENSITIVE RETINAL GANGLION CELLS: M1 CELLS AND NON-M1 CELLS
In primates, including humans, ipRGCs comprise only 0.2% of total retinal ganglion cells, which is about 3000 ipRGCs per eye . Within this small number is a surprising diversity of subtypes, which can be distinguished morphologically and physiologically. At this time, ipRGCs are classified into five subtypes [16▪▪,17]. The M1 cells, being the largest and most numerous subtype, correspond to the early descriptions of ipRGCs when they were still considered to be a uniform cell type [1–3]. M1 cells are rather large neurons having sparsely branched, long dendritic projections that stratify and interconnect in the outermost sublamina of the inner plexiform layer (IPL). M2 cells have larger soma and more complex dendritic arbours, which stratify in the innermost sublamina of the IPL [18–20]. The monostratified M1 and M2 cells constitute the majority of ipRGCs (up to 74–90%) [18,21]. The distinguishing morphologic feature of M3 cells is bistratification of their dendritic processes into both inner and outer sublamina of the IPL [21,22].
The most recently identified subtypes, M4 and M5, are rare cells that do not immunostain for melanopsin. They do, however, express marker proteins and can depolarize in the absence of any synaptic input . Morphologically, M4 cells have the largest soma of all ipRGCs and M5 cells have a wide, compact, highly branched dendritic arbour termed ‘bushy’, which stratifies into the outermost IPL layer .
CENTRAL PROJECTIONS OF INTRINSICALLY PHOTOSENSITIVE RETINAL GANGLION CELLS
In mice and primates, ipRGCs project monosynaptically to deep brain centres. One main target site is the suprachiasmatic nucleus (SCN) in the hypothalamus [2–4,23], which serves as the master circadian pacemaker. The retinal input to the SCN derives predominantly from the M1 subtype of ipRGCs [6,7,20]. The retinohypothalamic tract also projects to other brain regions related to circadian modulation, including the intergeniculate leaflet, the supraoptic nucleus, the ventral subparaventricular zone of the hypothalamus, the ventrolateral preoptic area and the lateral habenula [24–27].
M1 cells also project to the shell of the olivary pretectal nuclei (OPN) [17,20]. The outer shell corresponds to the location of OPN neurons that innervate the Edinger–Westphal nucleus, and thus would implicate M1 ipRGCs as the major and perhaps sole source of retinal light signalling for the pupil light reflex (PLR) . Recently, Chen et al. [28▪▪] demonstrated that M1 projections are linked to their expression of transcriptional factor Brn3b. Only Brn3b-positive M1 cells innervate the OPN outer shell; Brn3b-negative cells selectively innervate the SCN. Thus, despite its morphologic sameness, the M1 subtype is composed of two functionally distinctive subpopulations.
Non-M1 ipRGCs primarily innervate the core of the OPN, the dorsal lateral geniculate nucleus and the superior colliculus . These structures receive few, if any, fibres from M1 ipRGCs and are not directly involved in circadian regulation or pupillary responses to light.
MELANOPSIN AND THE INTRINSIC PHOTORESPONSE
Melanopsin photopigment is found in the soma, the dendrites and the proximal portion of the axon of ipRGCs. Their extensive dendritic arbours thus serve as important sites of intrinsic phototransduction. Interestingly, the expression of melanopsin in the retinas of rats show a diurnal modulation, with highest levels occurring near the end of the light period and lowest towards the end of the dark period . The relative sensitivity curve of mammalian melanopsin partly overlaps those of rods and cones and demonstrates a maximal sensitivity around 480 nm (blue light) .
Melanopsin-mediated depolarization of ipRGCs exhibits a sluggish photoresponse that is rather slow to reach peak firing rate [2,8,13]. Repolarization after light offset is also slow and cell spiking persists for some time after the light has been turned off. This slow response kinetic may be better suited to integrate information of ambient light levels over longer time periods . Another characteristic of the intrinsic response is its relative insensitivity to photic stimulation. This is explained by the sparse membrane density of melanopsin, which is about 104-fold lower than rod and cone pigments . Thus, ipRGCs alone are rather inefficient at absorbing light, and activation of their intrinsic photoresponse requires much higher irradiance than that needed for activating rods and cones.
The quantity of melanopsin expressed and the quality of the intrinsic photoresponse do vary among the ipRGC subtypes. M1 cells contain the highest quantities of melanopsin and have the largest, most sensitive intrinsic photoresponses [21,22]. The M2 and M3 subtypes have intermediate levels of melanopsin with significantly smaller intrinsic photoresponses than the M1 cells. Finally, M4 and M5 subtypes contain the lowest levels of melanopsin and produce weak, low-amplitude intrinsic photoresponses . Accordingly, M1 cells are driven mostly by their own intrinsic, melanopsin-mediated response to light, whereas the non-M1 cells are strongly influenced by synaptic (extrinsic) input from rods and, in particular, cones [17,22]. There is strong evidence that in all ipRGC subtypes, melanopsin regeneration occurs intracellularly on the basis of a bistable mechanism using longer wavelengths of light [31,32].
Although ipRGCs are capable of depolarizing directly to light stimulation, their activity is under constant influence of rods and cones via synaptic connections with bipolar cells. These extrinsic inputs allow ipRGCs to respond to light with shorter response times, larger depolarization and greater sensitivity to light than is possible from intrinsic melanopsin-mediated response alone. In this way, ipRGCs expand their ability to encode a very broad range of different light stimuli.
PUPIL LIGHT REFLEX: INTEGRATION OF ROD, CONE AND MELANOPSIN SIGNALS
In genetically modified mice, neither the absence of conventional phototransduction (rods and cones) nor of intrinsic phototransduction (melanopsin) alone will abolish the PLR [5,33]. In other words, rods, cones and melanopsin all contribute, via the ipRGCs, to the afferent pupillomotor signal relayed to the OPN [8,34,35]. However, at any given moment, the proportionate contribution of each photoreceptor system is dependent on the light condition. Broadly stated, the highly sensitive rod system dominates the PLR under conditions of dark adaptation. Cone intrusion occurs quickly with increasing stimulus light intensity and with light adaptation. Abrupt changes in illumination activate cones (and rods) whose rapid signalling of light onset and offset defines the recognizable PLR having a fast, transient pupillary constriction followed by a prompt redilation to baseline [6,35,36]. Melanopsin contribution leads to a more sustained modulation of steady-state pupil size [34,37,38]. Knockout models in mice have shown the influence of each photoreceptor in isolation on the PLR [5,33,39], but photoreceptor isolation in the healthy human individual is, at best, difficult due to the complex and nonlinear relationship between extrinsic (rods, cones) and intrinsic (melanopsin) inputs to the ipRGCs.
That said, there is nonetheless a renewed interest in the PLR as a means to assess retinal function noninvasively. By using different narrow-bandwidth (coloured) light stimuli presented under dark and light adaptation, the PLR can be weighted to favour rod, cone or melanopsin activation in humans [34,35,40,41]. In patients with retinitis pigmentosa, their rod-weighted and cone-weighted pupil responses are reduced compared with normal controls [42▪,43▪,44]. In advanced stages of disease, the PLR is more sensitive than standard electroretinography for detecting residual levels of photoreceptor activity [45,46]. Interestingly, the melanopsin-mediated pupil response is preserved in some patients with retinitis pigmentosa, whereas in others it is abnormally low [42▪,44,46]. The reasons for this differential response of inner retinal function are not yet elucidated. In some patients completely blind from end-stage outer retinal degeneration, a slow PLR can still be clinically observed. This pupil response is derived mainly from inner retinal (melanopsin-mediated) phototransduction  and explains why patients blind from rod and cone degeneration can retain a circadian rhythm [47,48].
In mammals including primates and humans, blue light of high irradiance (>13 log quanta/cm2/s retinal irradiance) can strongly activate melanopsin-dependent projections . The resulting PLR shows a longer latency and time to peak response than a PLR to an equiluminant red light, which is largely cone-driven [8,33,49]. Following termination of the blue, but not red, light stimulus, the pupil stays constricted. This prolongation of pupil constriction, termed the postillumination pupil response (PIPR), is mediated by melanopsin and corresponds to the previously described slow response kinetics of the intrinsic photoresponse [35,50].
It is not known whether the PIPR is driven exclusively by melanopsin and a standardized parameter to measure PIPR has not yet been established. Recent studies [43▪,50,51,52▪] have used different outcome parameters to measure PIPR, including mean poststimulus pupil size, area under the poststimulus pupil response curve, pupil size at 6 s after light offset, among others. The PIPR has a modulation across 24 h that is not observed in primarily cone-driven pupil responses [52▪,53▪]. In healthy humans, PIPR increases with age. This may be, in part, a compensatory response of ipRGCs to the relative loss of blue light transmission through an ageing lens .
PIPR is particularly appealing to clinicians as a behavioural measure of largely the melanopsin system and ipRGC activity because the pupil is a readily accessible marker that can be objectively measured using noninvasive techniques. In patients with glaucoma, PIPR has been found to be reduced at moderate and advanced stages of disease [55▪,56]. This would suggest that the neuronal death in glaucoma is nonselective and involves both conventional ganglion cells and ipRGCs. Reduction of ipRGC function, as assessed by PIPR, has also been reported in patients with diabetes, even in the absence of visible retinopathy .
THE INTRINSICALLY PHOTOSENSITIVE RETINAL GANGLION CELLS ARE THE CIRCADIAN PHOTORECEPTORS
Circadian photoentrainment regulates daily synchronization of the internal biological clock with the environmental 24-h light/dark cycle. As the mammalian biological master clock in the SCN receives a majority of its input from ipRGCs via the retinohypothalamic tract, circadian photo entrainment can still be operational in the absence of rods and cones . Conversely, genetically induced melanopsin deficiency in mice results in normal circadian photoentrainment to 12 h : 12 h light–dark cycles, but attenuated circadian phase shifts in response to a short blue light . Melanopsin also mediates the acute sleep-inducing effects of light  and impacts sleep homeostasis in mice . An important physiological marker for the circadian phase is plasma or saliva concentrations of the pineal gland hormone, melatonin. Its nocturnal secretion can be suppressed by light . The magnitude and direction of induced circadian phase shifts are dependent on the spectral composition of light, exposure duration, intensity and time of day .
Similar to circadian effects, nonimage-forming acute light responses are also mediated by ipRGCs. Those responses occur immediately and have short duration. Due to the blue-shifted sensitivity of ipRGCs, stronger responses to monochromatic blue than to green light (or red light) exposures were shown on acute melatonin suppression [64–68], alertness, core body temperature, heart rate, sleep architecture and electronencephalogram spectra, PLR, clock gene expression, cognitive performance, brain activity and emotional processing [35,67,69–75].
The substantial involvement of ipRGCs in acute and circadian light responses raises the question whether these cells or their projections, when damaged, contribute to human diseases and circadian misalignment. It has been observed that many blind patients suffer chronic sleep disturbances and insomnia [76,77]. This can be explained by the fact that certain optic neuropathies cause diffuse ganglion cell death, ipRGCs included, and thus disrupt both visual function and circadian rhythm. One such optic neuropathy is glaucoma. In an animal model for glaucoma, the circadian readjustment of activity rhythms to a shifted light–dark cycle takes significantly longer than in normal animals . Humans with glaucoma show attenuation of the PIPR to blue light (see above) [55▪,56] and respond with less melatonin suppression to nocturnal bright light exposure . In contrast, some optic neuropathies cause selective ganglion cell death. For example, Leber's hereditary optic neuropathy preferentially spares ipRGCs despite severe loss of conventional ganglion cells, thus explaining why circadian function is not impaired in these patients with optic neuropathy and severe visual disability . In addition, these patients can have a normal PLR  and show equal nocturnal melatonin suppression in response to bright light exposure, when compared with healthy controls .
Scheduled bright light therapy (up to 10 000 lx) can be therapeutically used to alleviate symptoms in many psychiatric and medical disorders [82▪]. A well known target group for light therapy are patients with seasonal affective disorders (SADs). These patients suffer from depressive symptoms, which typically manifest during the fall and winter season. SAD patients also show an abnormal response to light in the posterior hypothalamus , an altered electroretinogram  and a genetic missense variant in the melanopsin gene , suggesting that their ability to perceive light via ipRGC is altered. The therapy of choice for these patients is scheduled bright light therapy. Short-term bright light therapy, alone or in combination with medical treatment, is beneficial in many other psychiatric disorders, for example ante-partum depression [82▪], and for patients with dementia [86,87]. Recent results suggest that due to blue light sensitivity of ipRGCs and the potential involvement of melanopsin in mood regulation, low-intensity, blue-enriched light might be as effective in decreasing depressive symptoms as standard bright light treatment [88,89].
INTRINSICALLY PHOTOSENSITIVE RETINAL GANGLION CELLS AND PHOTOPHOBIA
The clinical observation that certain blind migraineurs can still experience light-induced exacerbation of headache  has long suggested that an alternative (nonrod, noncone) light-sensitive pathway is linked to the trigeminal pain system [91,92]. In mice with different types of photoreceptor dysfunction, light avoidance is not related to rod and cone function but rather to an intact melanopsin pathway . Conversely, mice whose melanopsin has been ablated do not demonstrate light avoidance and humans with bilateral enucleation do not experience photophobia , giving indirect evidence that ipRGCs are implicated and that the light signals mediating photophobia and other light-adverse reactions are carried via the optic nerve. Noseda et al. traced ipRGC axons to retinal axons to the dorsocaudal region of the posterior thalamus, and using extracellular single-unit recording, they showed that neurons in this nuclear group were dura-sensitive and also photosensitive . Thus, one mechanism for how light exacerbates migraine headache is convergence of light signals and nociceptive signals at the posterior thalamus, with resulting enhancement of the output signals to the somatosensory cortical areas that register pain. This and other studies continue to shed light on how ordinary light can initiate a variety of adverse and avoidance responses and may lead to more efficient means of treating photophobia.
DO INTRINSICALLY PHOTOSENSITIVE RETINAL GANGLION CELLS HAVE A ROLE IN VISUAL PERCEPTION?
In persons blind from retinal degeneration involving rods and cones, a vague awareness of images, motion or light perception is sometimes retained . Growing awareness of the extent of ipRGC projections to central nuclei that mediate spatial and discriminative visual functions [8,9,94] suggests that this phenomenon may have its origin in the melanopsin system. Ecker et al. found that in the absence of functional rods and cones, mice were still able to discriminate high-contrast gratings well enough to navigate a water maze, indicating that ipRGCs can support rudimentary image formation on the basis of pattern and spatial discrimination. In the most recent study to address this topic, Brown et al.[10▪▪] found that a melanopsin-based perception of brightness discrimination is active in mice with intact rods and cones as well as in normally sighted humans. Whether melanopsin also contributes to spatial information or any other aspect of subjective visual perception in humans is an exciting question whose answer may lead to new prospects for restoring vision in patients who lose vision from rod and cone disease.
The identification of ipRGCs has broadened and even changed traditional notions of how the eye processes and signals light information for both visual and nonvisual functions. Clinical implications of the melanopsin system are widespread, particularly as related to chronobiology.
Dr Münch is supported by the Velux Foundation (Switzerland).
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 105).
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