title: Muscarinic acetylcholine receptor-mediated stimulation of retinal ganglion cell photoreceptors.
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.
authors.affiliation: Department of Neuroscience, Ohio State University, Columbus, OH 43210, USA. Electronic address: Puneet.Sodhi@tufts.edu.
authors.forename: Puneet
authors.initials: P
authors.lastname: Sodhi
authors.affiliation: College of Optometry, Ohio State University, Columbus, OH 43210, USA. Electronic address: hartwick.4@osu.edu.
authors.forename: Andrew T E
authors.initials: AT
authors.lastname: Hartwick
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009924:Organ Culture Techniques; D010775:Photic Stimulation / Q000379:methods*; D010786:Photoreceptor Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D020318:Rats, Long-Evans / Q000469:parasitology; D011976:Receptors, Muscarinic / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000502:physiology*
chemical_list: D018679:Cholinergic Agonists; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D002217:Carbachol
keywords: 4-DAMP (PubChem CID: 3014059); AF-DX 384 (PubChem CID: 119356); Acetylcholine; Atropine (PubChem CID: 174174); Carbachol; Carbachol (PubChem CID: 5831); Flicker; Melanopsin; Muscarinic; Physostigmine (PubChem CID: 5983); Tubocurarine (PubChem CID: 6000); ipRGC (intrinsically photosensitive retinal ganglion cell)