Muscarinic acetylcholine receptor-mediated stimulation of retinal ganglion cell photoreceptors. (September 2016) - Sodhi, Puneet
Abstract: Melanopsin-dependent phototransduction in intrinsically photosensitive retinal ganglion cells (ipRGCs) involves a Gq -coupled phospholipase C (PLC) signaling cascade. Acetylcholine, released in the mammalian retina by starburst amacrine cells, can also activate Gq -PLC pathways through certain muscarinic acetylcholine receptors (mAChRs). Using multielectrode array recordings of rat retinas, we demonstrate that robust spiking responses can be evoked in neonatal and adult ipRGCs after bath application of the muscarinic agonist carbachol. The stimulatory action of carbachol on ipRGCs was a direct effect, as confirmed through calcium imaging experiments on isolated ipRGCs in purified cultures. Using flickering (6 Hz) yellow light stimuli at irradiances below the threshold for melanopsin activation, spiking responses could be elicited in ipRGCs that were suppressed by mAChR antagonism. Therefore, this work identified a novel melanopsin-independent pathway for stimulating sustained spiking in ganglion cell photoreceptors. This mAChR-mediated pathway could enhance ipRGC spiking responses in conditions known to evoke retinal acetylcholine release, such as those involving flickering or moving visual stimuli. Furthermore, this work identifies a pharmacological approach for light-independent ipRGC stimulation that could be targeted by mAChR agonists. Graphical abstract: Highlights: Carbachol stimulates sustained spiking in retinal ganglion cell photoreceptors. The effect of carbachol on ipRGCs is mediated by metabotropic muscarinic receptors. Carbachol's effect is direct, mediated by muscarinic receptors on ipRGCs themselves. Acetylcholine, released endogenously in the retina, can similarly stimulate ipRGCs. Cholinergic ipRGC stimulation can be evoked by relatively dim, flickering light stimuli.