Intrinsically photosensitive retinal ganglion cells: diversity of form and function.

Abstract

A subpopulation of retinal ganglion cells (RGCs) express the photopigment melanopsin, rendering them intrinsically photosensitive (ipRGCs). These ganglion cell photoreceptors are critical for several non-image forming behaviors including circadian entrainment and the pupillary light reflex. Initially thought to be a uniform population, later studies demonstrated that there was at least some degree of morphological and physiological diversity in the ipRGC population. Technical limitations, however, had prevented the comprehensive study of ipRGCs at the single cell level. The purpose of this project was to utilize a mouse model in which ipRGCs are labeled in vivo with enhanced green fluorescent protein to identify and target single ipRGCs for morphological and physiological analyses. The central hypothesis of the research presented herein is that distinct morphological ipRGC subtypes have distinct physiological properties and synaptic inputs, resulting in unique light information sent to target nuclei in the brain by the various ipRGC subpopulations. This work has confirmed the existence and further analyzed the morphological and physiological properties of at least three ipRGC subtypes: M1 cells with dendrites stratifying in the OFF sublamina of the inner plexiform layer (IPL), M2 cells with dendrites stratifying in the ON sublamina of the IPL, and M3 cells with dendrites bistratifying in both the ON and OFF sublaminas of the IPL. We find that these cell types do indeed possess distinct intrinsic light responses and intrinsic membrane properties. Furthermore, we find that these subpopulations are differentially influenced by cone-mediated signals. Finally, we find that the cation channel involved in ipRGC signal transduction is not composed solely of the canonical transient receptor potential channel (TRPC) subunit 3, 6, or 7. However, we do find that TRPC6 is involved in mediating the melanopsin-evoked light response in both M1 and M2 cells, with both subtypes showing a reduction in the magnitude of the intrinsic light response in TRPC6-/- animals. Collectively, the differential influence of intrinsic, melanopsin-mediated phototransduction and synaptically-evoked extrinsic inputs on the integrated light-evoked response of ipRGC subtypes indicates that these subtypes may serve as conduits for distinct light information sent to the brain. We discuss the implications of these findings and propose a model for the differential influence of distinct ipRGC subtypes on various non-image forming behaviors.