Intrinsically photosensitive retinal ganglion cells: to see, or not to see, that is the question

  In Chapter 4 of Principles of Neurobiology, we learned about the visual pathway from photoreceptors to retinal circuits to the visual cortex. Retinal ganglion cells (RGCs), the retina's output cells, transmit information from the eyes to the brain (Figure 4-2). RGCs extend dendrites into the inner plexiform layer and receive input from rods and cones via bipolar cells and amacrine cells. Their axons terminate in the thalamus's lateral geniculate nucleus, the superior colliculus, the pretectum, and the hypothalamus (Figure 4-37). There are more than 30 types of RGCs conveying information from a wide range of visual stimuli. Within numerous RGC types, intrinsically photosensitive retinal ganglion cells (ipRGCs), which express a particular G-protein-coupled receptor called melanopsin, remarkably play multiple functions in visual circuits (Section 4.19). ipRGCs not only integrate visual information from rods and cones, like other RGCs, but also directly sense light via the melanopsin. There are five subtypes of ipRGCs (M1–M5). M1 was the first discovered ipRGC subtype, which projects axons primarily to the suprachiasmatic nucleus (SCN) and plays an essential role in synchronizing the circadian oscillator (Section 9.13).

Over the past few years, researchers have found that other ipRGCs perform image-forming functions beyond the regulation of circadian rhythms (non-image-forming). Does the melanopsin phototransduction act through identical mechanisms in different ipRGC subtypes and the corresponding circuits? If not, how does the melanopsin phototransduction modulate image-forming functions in ipRGCs?

Previously, the Schmidt group reported that melanopsin null animals exhibit reduced behavioral contrast sensitivity (image-forming). However, where does the deficit originate in the visual pathway? Is it caused by ipRGCs (melanopsin-expressing)? In a new study, Sonoda et al. started by loose-patch recording in M4 ipRGCs and found that melanopsin enhances contrast sensitivity throughout a wide range of physiological light intensities, whereas melanopsin null M4 cells exhibit reduced contrast sensitivity.

Next, the authors performed whole-cell recording with different light levels to study how melanopsin phototransduction influences M4 cell physiology. They found that melanopsin phototransduction increases M4 ipRGC intrinsic excitability, whereas light background does not increase the excitability of melanopsin null M4 cells. They also found a melanopsin-dependent increase in input resistance and a decrease in leak conductance.

What is the channel that mediates the increased intrinsic excitability in M4 cells? Sonoda et al. measured the I–V relationship of the light response of M4 cells. The melanopsin photocurrent in M4 cells exhibited a negative slope relationship that reversed near –90 mV, close to the equilibrium potential of K⁺. In addition to the I–V relationship, their pharmacological data further implied that TASK two-pore domain (K2P) subfamily K⁺ channels are the likely candidates of the melanopsin phototransduction downstream. Combining these data above, the authors argued that M4 melanopsin increases the excitability via closure of K⁺ leak channels, a previously unidentified target of the melanopsin phototransduction cascade.

How does the melanopsin phototransduction cascade influence cellular contrast sensitivity at different light levels? Since melanopsin phototransduction cascade has been primarily examined in M1 cells, it has been widely assumed to couple to the Gq class of G-proteins, activate PLC, and open TRPC channels in all ipRGC subtypes. Chemogenetic (DREADD), pharmacological, and electrophysiological experiments revealed that the M4 cell melanopsin phototransduction cascade's initial steps are similar to those reported previously. Strikingly, Sonoda et al. found previously undescribed differential pathways, which could enhance contrast sensitivity, in late melanopsin phototransduction cascade at dim and bright light levels. In dim light, melanopsin phototransduction closes leak K⁺ channels, increasing input resistance. In bright light, melanopsin phototransduction closes leak potassium channels and opens TRPC channels (which are also the target channels for M1 cell melanopsin phototransduction pathway), leading to net depolarization of resting membrane potential and an increase in input resistance.

Schematic summary of melanopsin phototransduction mechanisms in M4 cells at dim and bright light levels (Rinp: input resistance). See Sonoda et al. for more details.

Sonoda et al. showed that melanopsin drives diverse physiological influences in ipRGC subtypes (M4 cell vs. M1 cell) specialized for different visual functions (image-forming vs. non-image-forming). These discoveries also raise many other interesting questions. Are there any other variations of the melanopsin phototransduction cascade in ipRGCs? How does melanopsin act within each ipRGC subtype? Are the divergent melanopsin phototransduction cascades in ipRGCs conserved in primates? Much has yet to be uncovered.

Reference

Sonoda T, Lee SK, Birnbaumer L, Schmidt TM., CMelanopsin phototransduction is repurposed by ipRGC subtypes to shape the function of distinct visual circuits. Neuron 99(4):754-767 (2018). Link