Burning the candle at both ends: Intraretinal signaling of intrinsically photosensitive retinal ganglion cells

Abstract

Intrinsically photosensitive retinal ganglion cells (ipRGCs) are photoreceptors located in the ganglion cell layer. They project to brain regions involved in predominately non-image-forming functions including entrainment of circadian rhythms, control of the pupil light reflex, and modulation of mood and behavior. In addition to possessing intrinsic photosensitivity via the photopigment melanopsin, these cells receive inputs originating in rods and cones. While most research in the last two decades has focused on the downstream influence of ipRGC signaling, recent studies have shown that ipRGCs also act retrogradely within the retina itself as intraretinal signaling neurons. In this article, we review studies examining intraretinal and, in addition, intraocular signaling pathways of ipRGCs. Through these pathways, ipRGCs regulate inner and outer retinal circuitry through both chemical and electrical synapses, modulate the outputs of ganglion cells (both ipRGCs and non-ipRGCs), and influence arrangement of the correct retinal circuitry and vasculature during development. These data suggest that ipRGC function plays a significant role in the processing of image-forming vision at its earliest stage, positioning these photoreceptors to exert a vital role in perceptual vision. This research will have important implications for lighting design to optimize the best chromatic lighting environments for humans, both in adults and potentially even during fetal and postnatal development. Further studies into these unique ipRGC signaling pathways could also lead to a better understanding of the development of ocular dysfunctions such as myopia.

Keywords: intraretinal; intrinsically photosensitive retinal ganglion cells (ipRGCs); melanopsin; retina; retinal processing.

FIGURE 1

ipRGC subtypes. A, Schematic of the mouse retina with the 6 melanopsin subtypes and their stratification in the inner plexiform layer (IPL) depicted. M1 ipRGC subtype is further divided into Brn3b positive and negative, and displaced M1s (dM1). Retinal pigment epithelium (RPE), outer segment (OS), outer nuclear layer (ONL), outer plexiform layer (OPL), inner nuclear layer (INL), ganglion cell layer (GCL), rods (R), cones (C), bipolar cell (BC), amacrine cell (AC), horizontal cell (HC). Image was created with BioRender.com.

FIGURE 2

Summary of hypothesized ipRGC intraretinal connectivity of M5 ipRGCs in the mouse retina. (A) M5 to corticotropin-releasing hormone-expressing amacrine cell (CRH⁺ AC) electrical coupling (resistor symbol), in addition to glutamate-mediated excitatory input to both M5 ipRGCs and CRH ACs (originating from rods and cones), drives GABA and CRH release from CRH ACs. (B1) Strong (thick magenta lines) feedforward GABAergic inhibition of M4 ipRGCs and a suppressed-by-contrast (SbC) RGC from an M5 coupled CRH⁺ AC; modest (thin magenta) GABAergic feedback inhibition to an electrically coupled M5 ipRGC. (B2), M5 ipRGC electrically coupled to a CRH + AC drives feedforward inhibition of a wide-field amacrine cell (WAC) that is electrically coupled to an M2 ipRGC. Reproduced with permission from Pottackal et al. (2021).

FIGURE 3

Summary of ipRGC intraretinal signaling routes in the retina. (Left) Chemical synaptic transmission to amacrine cells (AC) is either direct, via axon collaterals (Joo et al., 2013), or indirect via intermediary amacrines. (Middle) Direct gap junction connection of ipRGCs to amacrine cells in the GCL and INL in adult retina. Direct gap junction connection of ipRGC to amacrine cells (Muller et al., 2010; Reifler et al., 2015; Harrison et al., 2021; Pottackal et al., 2021), and ipRGC to ipRGCs and non-ipRGCs, during retinal development (Arroyo et al., 2016; Caval-Holme et al., 2019). (Right) Putative synaptic inputs to cone photoreceptor terminals in the OPL via outer retinal dendrites (ORDs) from M1 ipRGCs (Renna et al., 2015; Sondereker et al., 2017). Outer nuclear layer (ONL), outer plexiform layer (OPL), inner nuclear layer (INL), inner plexiform layer (IPL), ganglion cell layer (GCL), rods (R), cones (C), bipolar cell (BC), displaced amacrine cell (dAC), displaced M1 ipRGC (dM1). Created with BioRender.com.