Anatomy of ganglion-cell photoreceptors

Intrinsically photosensitive retinal ganglion cells (ipRGCs) are the only cells in the mammalian retina that express the photopigment protein melanopsin.  Melanopsin is found throughout cell body and dendrites of ipRGCs  (Provencio et al., 2002; Hattar et al., 2002), where it is almost entirely restricted to the plasma membrane (Belenky et al., 2003). Immunohistochemical staining for melanopsin is therefore an efficient way to assess the numbers, distribution and somadendritic morphology of ipRGCs.  Another source of information about their morphology comes from intracellular dye filling of physiologically identified ipRGCs (Berson et al., 2002; Lucas et al., 2003; Warren et al., 2003; Dacey et al., 2005)

 Melanopsin-expressing RGCs have been observed in a wide variety of mammals, including mice, rats, hamsters, blind mole rats, rabbits, monkeys and humans. In rodents, approximately 1000-2000 retinal ganglion cells (RGCs), about 1-3% of all RGCs, contain melanopsin (Hattar et al., 2002). Most reside in the ganglion cell layer, but a few are displaced to the inner nuclear layer (Provencio et al., 2000; Hattar et al., 2002; Hannibal & Fahrenkrug, 2002).  Melanopsin-positive RGCs are present throughout the retina, with somewhat higher density superiorly (Hattar et al., 2002; Hannibal & Fahrenkrug, 2002). Their dendrites form an extensively overlapping plexus in the inner plexiform layer (IPL; Hattar et al., 2002; Provencio et al., 2002; Dacey et al., 2005).  Dendritic trees of individual ipRGCs are large, spanning about 500 mm or 15 degrees of visual angle in the rat retina (Berson et al., 2002). Because the dendrites of these cells are photosensitive, the receptive fields of their intrinsic photoresponses are also large. This permits extensive spatial integration of light energy, initiating a process of spatial convergence that culminates in the huge receptive fields of SCN neurons (Groos & Mason, 1980). 

There is growing evidence for multiple subtypes of melanopsin-expression RGCs, distinguishable on the basis of the level of dendritic stratification within the inner plexiform layer (IPL).  Here, we consider only the most easily detected and fully characterized of these, which we call ‘M1 cells.’  These cells correspond to the ipRGCs that have been shown to project directly to the SCN (Berson et al., 2002; Lucas et al., 2003; Warren et al. 2003).  The dendrites of M1 cells arborize mainly in the outermost sublayer of the IPL, and are the source of the prominent plexus of melanopsin immunoreactive dendrites there (Berson et al., 2002; Hannibal & Fahrenkrug, 2002; Hattar et al., 2002; Provencio et al., 2002). In rodents, most M1 cells have cell bodies in the ganglion cell layer, but a few are displaced to the inner nuclear layer. (In primates, such displacement may be the rule, rather than the exception; see Dacey et al., 2005).  The dendritic stratification of M1 cells in the outer IPL is anomalous because both their intrinsic and synaptically mediated responses to light are essentially depolarizing (i.e., they are ‘ON responses’), whereas the outer IPL is considered the OFF sublayer, in which the axon terminals of OFF bipolar cells synapse upon the dendrites of OFF RGCs.  M1 ipRGCs also selectively express pituitary adenylate cyclase activating peptide (PACAP) and apparently release it in the SCN to affect the circadian system (Hannibal et al., 2002; Hannibal, 2002).

 In mice and monkeys, a second plexus of melanopsin-immunoreactive dendrites occupies the innermost IPL (Provencio et al., 2002; Dacey et al., 2005).  There is evidence in the monkey that the melanopsin cells from which these dendrites arise are ipRGCs, but his has not been proven in rodents.  The central projections of these cells, which we call ‘M2 cells,’ are unknown, but they do not appear to make a major contribution to the retinohypothalamic tract.

 Melanopsin-immunoreactive dendrites have been shown by electron microscopy to receive synaptic contacts in the IPL.  These include ribbon synapses from bipolar terminals, and these are apparently restricted to the proximal dendrites of ipRGCs in the ON sublayer of the IPL. There are also conventional synaptic contacts from amacrine cells (Belenky et al., 2003).