Shijun Weng

Form and function of the M4 cell, an intrinsically photosensitive retinal ganglion cell type contributing to geniculocortical vision.

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 α 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 inner plexiform layer. 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 nonlinear 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.

Circadian modulation of melanopsin-driven light response in rat ganglion-cell photoreceptors

Intrinsically photosensitive retinal ganglion cells (ipRGCs) project to the suprachiasmatic nucleus (SCN) and are essential for normal photic entrainment of global circadian rhythms in physiology and behavior. The effect of light on the central clock is dependent on circadian phase, and the retina itself contains intrinsic circadian oscillators that can alter its sensitivity to light. This raises the possibility that the ipRGCs, and hence the photoentraining signals in the retinohypothalamic tract, are subject to circadian modulation. Although the ipRGC photopigment melanopsin reportedly exhibits circadian variations in expression, there has been no direct test of the hypothesis that ipRGC sensitivity is under circadian control. Here, the authors provide such a test by measuring the sensitivity of intrinsic photoresponses of rat ipRGCs at 4 circadian times (CTs) using multielectrode array recording. There was little if any circadian modulation in the threshold of intrinsic ipRGC photoresponses. However, very bright light evoked significantly more spiking early in the subjective night (CT12-13) than at other circadian phases. Thus, the gain of the melanopsin-driven response is slightly increased in the early night, at roughly the circadian phase when melanopsin synthesis is thought to be elevated. However, this gain change is probably too modest to contribute much to shape the phase response curve (PRC) for behavioral photoentrainment.

Light acts through melanopsin to alter retinal waves and segregation of retinogeniculate afferents

Waves of correlated activity sweeping across the early postnatal mouse retina promote the segregation and refinement of retinofugal projections. This process has been thought to be spontaneous and unaffected by visual experience. We found, however, that light prolongs spiking during the waves and enhances the segregation of retinogeniculate afferents, and that it did so by activating melanopsin-expressing, intrinsically photosensitive retinal ganglion cells.

Mouse Ganglion-Cell Photoreceptors Are Driven by the Most Sensitive Rod Pathway and by Both Types of Cones

Intrinsically photosensitive retinal ganglion cells (ipRGCs) are depolarized by light by two mechanisms: directly, through activation of their photopigment melanopsin; and indirectly through synaptic circuits driven by rods and cones. To learn more about the rod and cone circuits driving ipRGCs, we made multielectrode array (MEA) and patch-clamp recordings in wildtype and genetically modified mice. Rod-driven ON inputs to ipRGCs proved to be as sensitive as any reaching the conventional ganglion cells. These signals presumably pass in part through the primary rod pathway, involving rod bipolar cells and AII amacrine cells coupled to ON cone bipolar cells through gap junctions. Consistent with this interpretation, the sensitive rod ON input to ipRGCs was eliminated by pharmacological or genetic disruption of gap junctions, as previously reported for conventional ganglion cells. A presumptive cone input was also detectable as a brisk, synaptically mediated ON response that persisted after disruption of rod ON pathways. This was roughly three log units less sensitive than the rod input. Spectral analysis revealed that both types of cones, the M- and S-cones, contribute to this response and that both cone types drive ON responses. This contrasts with the blue-OFF, yellow-ON chromatic opponency reported in primate ipRGCs. The cone-mediated response was surprisingly persistent during steady illumination, echoing the tonic nature of both the rod input to ipRGCs and their intrinsic, melanopsin-based phototransduction. These synaptic inputs greatly expand the dynamic range and spectral bandpass of the non-image-forming visual functions for which ipRGCs provide the principal retinal input.

A subset of iprgcs regulates both maturation of the circadian clock and segregation of retinogeniculate projections in mice

The visual system consists of two major subsystems, image-forming circuits that drive conscious vision and non-image-forming circuits for behaviors such as circadian photoentrainment. While historically considered non-overlapping, recent evidence has uncovered crosstalk between these subsystems. Here, we investigated shared developmental mechanisms. We revealed an unprecedented role for light in the maturation of the circadian clock and discovered that intrinsically photosensitive retinal ganglion cells (ipRGCs) are critical for this refinement process. In addition, ipRGCs regulate retinal waves independent of light, and developmental ablation of a subset of ipRGCs disrupts eye-specific segregation of retinogeniculate projections. Specifically, a subset of ipRGCs, comprising ~200 cells and which project intraretinally and to circadian centers in the brain, are sufficient to mediate both of these developmental processes. Thus, this subset of ipRGCs constitute a shared node in the neural networks that mediate light-dependent maturation of the circadian clock and light-independent refinement of retinogeniculate projections. DOI: http://dx.doi.org/10.7554/eLife.22861.001

RdgB2 is required for dim-light input into intrinsically photosensitive retinal ganglion cells

Intrinsically photosensitive retinal ganglion cells (ipRGCs) are directly activated by bright light and indirectly by light relayed from rods and cones. This relay depends on RDGB2, and circadian photoentrainment and the pupillary light response are reduced in RdgB2−/− animals under low light. RDGB2 is required to transduce light input from rods to ipRGCs.