Intrinsically photosensitive retinal ganglion cells: many subtypes, diverse functions

Abstract

For decades, rods and cones were thought to be the only photoreceptors in the mammalian retina. However, a population of atypical photoreceptive retinal ganglion cells (RGCs) expresses the photopigment melanopsin and is intrinsically photosensitive (ipRGCs). These ipRGCs are crucial for relaying light information from the retina to the brain to control circadian photoentrainment, pupillary light reflex, and sleep. ipRGCs were initially described as a uniform population involved solely in signaling irradiance for non-image forming functions. Recent work, however, has uncovered that ipRGCs are unexpectedly diverse at the molecular, cellular and functional levels, and could even be involved in image formation. This review summarizes our current understanding of the diversity of ipRGCs and their various roles in modulating behavior.

Figure 1

Schematic diagram illustrating the connectivity and location of the five distinct morphological subtypes (M1–M5) of ipRGCs and projections to their predominant targets in the brain. The mammalian retina contains three nuclear layers (outer, inner and ganglion) and two plexiform layers (outer and inner). Synaptic connections between photoreceptors (rods and cones), horizontal and bipolar cells (BC) occur in the outer plexiform layer, whereas synaptic connections between bipolar, amacrine and ganglion cells occur in the inner plexiform layer (IPL). The outer nuclear layer contains the classical photoreceptors rods and cones (shown in gray). The inner nuclear layer (INL) contains horizontal cells (not shown), bipolar, and amacrine cells, of which only dopaminergic amacrine cells (DAC) are shown. The ganglion cell layer contains conventional ganglion cells (not shown) and the ipRGCs. For simplicity, M1 ipRGCs displaced to the INL [6] are not depicted in this diagram. M1 ipRGCs stratify in the OFF sublamina (red); M2, M4, M5, stratify in the ON sublamina (blue); and M3, stratify in the ON and OFF sublamina (purple) of the IPL of the retina. M4 ipRGCs have the largest cell body size, and M1 cells have smaller body size than M2–M4 cells [20, 24, 25]. The cell body size of M5 is not known (dotted line). The proportion of ON and OFF stratification in M3 ipRGCs varies considerably between cells [25]. Recent findings suggest that the M1 subtype consists of two distinct subpopulations that are molecularly defined by the expression of the Brn3b transcription factor [89]. Red dots indicate synaptic connections for which both functional and anatomical evidence exists [22, 28, 32, 33, 35]. Blue dots indicate synaptic connections for which either functional or anatomical evidence exists [24, 25, 38, 39]. ipRGC subtypes project to distinct non-image and image-forming nuclei in the brain [9, 24]. M1cells predominantly project to non-image forming centers such as the suprachiasmatic nucleus (SCN) to control circadian photoentrainment and the shell of the olivary pretectal nucleus (OPN) to control the pupillary light reflex. M1 innervation of brain targets could be further divided by Brn3b expression with Brn3b-negative (Brn3b-) M1 ipRGCs predominantly projecting to the SCN [89]. M3 brain targets are completely unknown at this time. M2, M4 and M5 are included together since no specific genetic marker exists for a single subtype. Collectively, they project to image forming areas in the brain such as the lateral geniculate nucleus (LGN) and the superior colliculus (SC), but also to the core of the OPN of which no specific function is assigned to this brain region [24, 85]. Retrograde analysis confirms that M2 cells project minimally to the SCN and strongly to the OPN [18].

Figure 2

A proposed pathway for chromophore regeneration in ipRGCs. This figure provides a simplified summary of chromophore regeneration (the visual cycle) for vertebrate cones [rods use only the retinal pigmented epithelium (RPE) pathway], Drosophila photoreceptors, and a proposed pathway for ipRGCs. Photopigments of rods and cones composed of the opsin and the chromophore (11-cis retinal; 11-CRAL) respond to light through the absorption of photon energy by the 11-CRAL which is then converted to all trans retinal (ATRAL) leading to the activation of the opsin’s G-protein pathway. ATRAL dissociates from the opsin and is first converted to the alcohol form (ATROL) in the photoreceptors and then transported to the RPE. In the RPE, the ATROL is converted back through an RPE65 dependent multistep process to 11-CRAL. Recent studies showed that cones also use Müller glia to convert ATROL to 11-CROL, which is then converted to 11-CRAL within cones. Dotted line indicates multiple steps that are not depicted in this figure for simplicity. Note that only in Drosophila and ipRGCs, the trans form of the chromophore (3-OH-ATRAL and ATRAL, respectively) can be converted back to the cis form (3-OH-11-CRAL and 11-CRAL, respectively) in the photoreceptors by exposure to long wavelength light (orange light for Drosophila photoreceptors and red light for ipRGCs). Recent discovery in Drosophila revealed an alternative pathway that depends on pigment cells for chromophore regeneration, where similar to vertebrate rods and cones, all trans form is converted to the cis form outside the photoreceptor itself. The site of conversion from the alcohol to the cis form is currently unknown, hence depicted by a question mark. We propose that ipRGCs also use a chromophore regeneration pathway requiring the Müller glia, similar to cones. Red lines indicate proposed steps for chromophore regeneration in ipRGCs and question marks indicate that these pathways have not been demonstrated, although the dependence of ipRGCs on RPE65 is well documented [62].

Figure 3

Schematic diagram illustrating the behavioral functions attributed to ipRGCs (M1 and non-M1) and the relative contribution of conventional RGCs to various behaviors. White boxes indicate functions that have been demonstrated to depend on a specific class of ipRGC and/or RGC. Gray boxes indicate functions that are ipRGC dependent, but the relative contribution of individual ipRGC subtypes has not been fully resolved. The role of M1-Brn3b-negative ipRGCs for circadian photoentrainment and the M1-Brn3b-positive ipRGCs for pupillary light reflex is the best documented [89]. The individual contribution of M2–M5 ipRGCs to specific functions is currently unknown and these subtypes are hence grouped together as non-M1 ipRGCs. Conventional RGCs, secondarily through rods and cones, influence higher cognitive functions, attention, pattern and color vision. Based on retinal recordings and brain innervation patterns, non-M1 cells may contribute to higher cognitive functions, pattern and color vision [24, 29, 85, 86]. Mood is known to be affected by light (as in seasonal affective disorder [SAD]). However, the contributions of ipRGCs and conventional RGCs to mood are not yet resolved, although an association between a mutant variant of melanopsin and SAD was recently described [84]. Melanopsin phototransduction is capable of relaying light signals to influence migraine photophobia in the absence of classical vision, but the contribution of each subtype is currently unknown [88]. For both sleep and alertness, melanopsin phototransduction is absolutely required for the light and dark effects on both functions, but again the individual contribution of ipRGC subtypes is unknown [82]. Finally, neonatal light avoidance requires melanopsin-based photoreception [71]. Based on morphological analysis during development [73], the neonatal avoidance task is most likely mediated by non-M1 ipRGCs, although this has not yet been shown directly.