UC San Diego

Melanopsin-expressing retinal ganglion cells (mRGC) are intrinsically photosensitive and combine their melanopsin-based photoresponses with rod and cone signals to convey light information to a subset of retinal brain targets. mRGC axons to non-image forming (NIF) visual centers are essential for the proper functioning of processes like circadian photoentrainment and pupillary light reflex. Surprisingly, mRGCs also send axons to image-forming regions of the brain. It is unknown how mRGCs mediate such diverse functions.

Classically, a cell’s morphology and location in a biological system is a direct reflection of its synaptic connections and, by definition, their function. mRGCs can be divided into five subtypes (M1-M5) based on morphology and dendritic stratification in the inner plexiform layer. In the classical sense, since M1s send axons to only a subset of mRGC-target regions and are the only subtype that monostratify in the OFF-sublamina, M1s likely serve a distinct function from other subtypes. However, M1s, like all mRGCs, exhibit an ON-response. This reveals a hole in what we understand about intraretinal connectivity and attenuates the weight that should be afforded to stratification in determining function. While the other mRGC subtypes have distinct morphology and branching patterns, it is unknown whether they serve specific functions. Thus, in order to explore the structure-function relationship of mRGC subtypes, we must consider connectivity. Unfortunately, the variable expression of melanopsin protein between subtypes and across the architecture of a single mRGC and the lack of unique markers for up- and downstream interactors has precluded rigorous study of mRGC connectivity in the retina and central targets.

We use a correlated light and electron microscopy label and serial blockface scanning electron microscopy to explore the architecture and synaptic partners of mRGCs in an attempt to better understand the connectivity of mRGC subtypes. We show significant differences in the ultrastructure of mRGC axonal terminals in mRGC-recipient brain regions, stratification-specific differences in mRGC dendrites, and catalog the intraretinal connections specific to mRGC subtypes.