Expression and Function of the Endocannabinoid System in the Retina and the Visual Brain

Abstract

Endocannabinoids are important retrograde modulators of synaptic transmission throughout the nervous system. Cannabinoid receptors are seven transmembrane G-protein coupled receptors favoring Gi/o protein. They are known to play an important role in various processes, including metabolic regulation, craving, pain, anxiety, and immune function. In the last decade, there has been a growing interest for endocannabinoids in the retina and their role in visual processing. The purpose of this review is to characterize the expression and physiological functions of the endocannabinoid system in the visual system, from the retina to the primary visual cortex, with a main interest regarding the retina, which is the best-described area in this system so far. It will show that the endocannabinoid system is widely present in the retina, mostly in the through pathway where it can modulate neurotransmitter release and ion channel activity, although some evidence also indicates possible mechanisms via amacrine, horizontal, and Müller cells. The presence of multiple endocannabinoid ligands, synthesizing and catabolizing enzymes, and receptors highlights various pharmacological targets for novel therapeutic application to retinal diseases.

Figure 1

Schematic illustration representing the organization of the mouse retina. Rod (R) and cone (blue/C) photoreceptors have their cell bodies in the outer nuclear layer (ONL) and extend inner (IS) and outer (OS) segments. Photoreceptors axons synapse in the outer plexiform layer (OPL) with horizontal (yellow/H) and bipolar (magenta/RBC-CBC) cells. The inner nuclear layer (INL) also contains amacrine (red/A) and Müller cells (M). Bipolar cells synapse to amacrine and ganglion (blue/G) cells in the inner plexiform layer (IPL). Ganglion cell axons form the optic nerve in the ganglion cell layer (GCL) and carry signals to the brain.

Figure 2

Schematic illustration representing the distribution of CB1R in the adult retina of several species. CB1R expression was demonstrated in dark gray retinal cells, while CB1R presence was noted in light gray retinal layers without precise localization. OS, outer segments of photoreceptors; IS, inner segments of photoreceptors; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer; C, cones; R, rods; H, horizontal cells; CBC, cone bipolar cells; RBC, rod bipolar cells; A, amacrine cells; G, ganglion cells; M, Müller cells.

Figure 3

Schematic illustration showing the expression of CB2R in the adult retina of several species. CB1R expression was demonstrated in dark gray retinal cells, while CB2R presence was noted in light gray retinal layers without precise localization. OS, outer segments of photoreceptors; IS, inner segments of photoreceptors; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer; C, cones; R, rods; H, horizontal cells; CBC, cone bipolar cells; RBC, rod bipolar cells; A, amacrine cells; G, ganglion cells; M, Müller cells. Scale bar: 20 μm.