Form and Function of the M4 Cell, an Intrinsically Photosensitive Retinal Ganglion Cell Type Contributing to Geniculocortical Vision

Abstract

The photopigment melanopsin confers photosensitivity upon a minority of retinal output neurons. These intrinsically photosensitive retinal ganglion cells (ipRGCs) are more diverse than once believed, comprising five morphologically distinct types, M1 through M5. Here, in mouse retina, we provide the first in-depth characterization of M4 cells, including their structure, function and central projections. M4 cells apparently correspond to ON alpha cells of earlier reports, and are easily distinguished from other ipRGCs by their very large somata. Their dendritic arbors are more radiate and highly branched than those of M1, M2 or M3 cells. The melanopsin-based intrinsic photocurrents of M4 cells are smaller than those of M1 and M2 cells, presumably because melanopsin is more weakly expressed; we can detect it immunohistochemically only with strong amplification. Like M2 cells, M4 cells exhibit robust, sustained synaptically-driven ON responses and dendritic stratification in the ON-sublamina of the IPL. However, their stratification patterns are subtly different, with M4 dendrites positioned just distal to those of M2 cells and just proximal to the ON cholinergic band. M4 receptive fields are large, with an ON center, antagonistic OFF surround, and non-linear spatial summation. Their synaptically-driven photoresponses lack direction selectivity and show higher ultraviolet sensitivity in the ventral retina than in the dorsal retina, echoing the topographic gradient in S- and M-cone opsin expression. M4 cells are readily labeled by retrograde transport from the dorsal lateral geniculate nucleus, and thus likely contribute to the pattern vision that persists in mice lacking functional rods and cones.

Signalling by melanopsin (OPN4) expressing photosensitive retinal ganglion cells

“…To date at least five distinct subtypes of pRGC have been identified, termed M1-M5-type pRGCs. 1,2,[32][33][34][35] These cells show differences in morphology and retinal connections, and exhibit light responses with markedly different kinetics and sensitivities ( Figure 1b) [32][33][34][37][38][39] (Figure 1c), and would therefore seem to be tasked with performing different physiological roles (for review see Schmidt et al 36,40 ). However, the innervations of each class of pRGC are only partially resolved, and the specific roles performed by each class of pRGC are yet to be fully determined.…”

“…Some information is available from studies using retrograde labelling from key structures, including the SCN, OPN, and SC, showing that the SCN is innervated primarily by M1-type pRGCs (80%) with lower innervations by M2-type cells (20%), 34 the OPN receives input from both M1 (55%, mainly shell region) and M2 cells (45%, mainly core region), 34 whereas the SC receives input from M1-M5 cells, 46 and the dLGN is innervated primarily by M4-type pRGCs but also receives input from other non-M1 pRGCs but not M1-type pRGCs. 39 …”

“…The nature and properties of light responses recorded from cells within the dLGN have suggested a role for melanopsin in encoding changes in background [18][19][20] and the modulation of visual responses, with melanopsin reportedly driving adaptation of visual responses, modulating visual feature selectivity and facilitating a more reliable encoding of complex visual signals. 22,23 Based on retrograde labelling studies, it would seem that M4-type pRGCs project almost exclusively to the dLGN, 39 and would, therefore, seem to be predominantly tasked with providing input to visual pathways. In keeping with this hypothesis, M4-type pRGCs have now been identified as a subset of alpha ON ganglion cells, 21,39 a type of retinal ganglion cell known to be involved in the processing of visual information and contrast sensitivity.…”

“…In keeping with this hypothesis, M4-type pRGCs have now been identified as a subset of alpha ON ganglion cells, 21,39 a type of retinal ganglion cell known to be involved in the processing of visual information and contrast sensitivity. 21 However, the dLGN also receives input from other non-M1-type pRGCs, 39 and thus, it has been difficult to determine the specific contribution of each pRGC subtype to these responses.…”

“…67 Responses of pRGCs may also be spectrally tuned depending on their location in the retina. 39,44 Thus it seems plausible that individual pRGCs are capable of generating responses with different properties under specific conditions, significantly adding to the diversity of signals generated by melanopsin signalling.…”