title: M1 ipRGCs Influence Visual Function through Retrograde Signaling in the Retina.
abstract: Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs, with five subtypes named M1-M5) are a unique subclass of RGCs with axons that project directly to many brain nuclei involved in non-image-forming functions such as circadian photoentrainment and the pupillary light reflex. Recent evidence suggests that melanopsin-based signals also influence image-forming visual function, including light adaptation, but the mechanisms involved are unclear. Intriguingly, a small population of M1 ipRGCs have intraretinal axon collaterals that project toward the outer retina. Using genetic mouse models, we provide three lines of evidence showing that these axon collaterals make connections with upstream dopaminergic amacrine cells (DACs): (1) ipRGC signaling to DACs is blocked by tetrodotoxin both in vitro and in vivo, indicating that ipRGC-to-DAC transmission requires voltage-gated Na(+) channels; (2) this transmission is partly dependent on N-type Ca(2+) channels, which are possibly expressed in the axon collateral terminals of ipRGCs; and (3) fluorescence microscopy reveals that ipRGC axon collaterals make putative presynaptic contact with DACs. We further demonstrate that elimination of M1 ipRGCs attenuates light adaptation, as evidenced by an impaired electroretinogram b-wave from cones, whereas a dopamine receptor agonist can potentiate the cone-driven b-wave of retinas lacking M1 ipRGCs. Together, the results strongly suggest that ipRGCs transmit luminance signals retrogradely to the outer retina through the dopaminergic system and in turn influence retinal light adaptation.
  
  
  
  Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) comprise a third class of retinal photoreceptors that are known to mediate physiological responses such as circadian photoentrainment. However, investigation into whether and how ipRGCs contribute to vision has just begun. Here, we provide convergent anatomical and physiological evidence that axon collaterals of ipRGCs constitute a centrifugal pathway to DACs, conveying melanopsin-based signals from the innermost retina to the outer retina. We further demonstrate that retrograde signals likely influence visual processing because elimination of axon collateral-bearing ipRGCs impairs light adaptation by limiting dopamine-dependent facilitation of the cone pathway. Our findings strongly support the hypothesis that retrograde melanopsin-based signaling influences visual function locally within the retina, a notion that refutes the dogma that RGCs only provide physiological signals to the brain.
authors.affiliation: Eye Research Institute, Oakland University, Rochester, Michigan 48309.
authors.forename: Cameron L
authors.identifier: 0000-0002-8657-0236
authors.initials: CL
authors.lastname: Prigge
authors.affiliation: Department of Life Science, National Taiwan University, Taipei, Taiwan 10617.
authors.forename: Po-Ting
authors.initials: PT
authors.lastname: Yeh
authors.affiliation: Department of Life Science, National Taiwan University, Taipei, Taiwan 10617.
authors.forename: Nan-Fu
authors.identifier: 0000-0002-5353-5477
authors.initials: NF
authors.lastname: Liou
authors.affiliation: Department of Life Science, National Taiwan University, Taipei, Taiwan 10617.
authors.forename: Chi-Chan
authors.identifier: 0000-0001-7880-6774
authors.initials: CC
authors.lastname: Lee
authors.affiliation: Department of Life Science, National Taiwan University, Taipei, Taiwan 10617.
authors.forename: Shih-Feng
authors.identifier: 0000-0001-8713-3815
authors.initials: SF
authors.lastname: You
authors.affiliation: Eye Research Institute, Oakland University, Rochester, Michigan 48309.
authors.forename: Lei-Lei
authors.identifier: 0000-0002-8158-7266
authors.initials: LL
authors.lastname: Liu
authors.affiliation: Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218, and.
authors.forename: David S
authors.identifier: 0000-0002-6892-5902
authors.initials: DS
authors.lastname: McNeill
authors.affiliation: Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218, and.
authors.forename: Kylie S
authors.identifier: 0000-0003-4752-009X
authors.initials: KS
authors.lastname: Chew
authors.affiliation: Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218, and.
authors.forename: Samer
authors.initials: S
authors.lastname: Hattar
authors.affiliation: Department of Life Science, National Taiwan University, Taipei, Taiwan 10617, Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan 10617 zhang@oakland.edu alenskchen@ntu.edu.tw.
authors.forename: Shih-Kuo
authors.identifier: 0000-0002-7921-1358
authors.initials: SK
authors.lastname: Chen
authors.affiliation: Eye Research Institute, Oakland University, Rochester, Michigan 48309, zhang@oakland.edu alenskchen@ntu.edu.tw.
authors.forename: Dao-Qi
authors.identifier: 0000-0002-2942-4128
authors.initials: DQ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics / Q000378:metabolism; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism; D008027:Light; D008297:Male; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012160:Retina / Q000166:cytology*; D012165:Retinal Ganglion Cells / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D017299:Rod Opsins / Q000235:genetics / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D015293:Transducin / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D014785:Vision, Ocular / Q000235:genetics / Q000502:physiology*; D014795:Visual Pathways / Q000502:physiology*; D001616:beta-Galactosidase / Q000378:metabolism; D000099210:Melanopsin
chemical_list: D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D054815:Cyclic Nucleotide-Gated Cation Channels; D044385:GTP-Binding Protein alpha Subunits; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D017299:Rod Opsins; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D015293:Transducin; D014446:Tyrosine 3-Monooxygenase; D001616:beta-Galactosidase; D000099210:Melanopsin; C518237:Cnga3 protein, mouse; C488949:Gnat1 protein, mouse; C517438:Pde6b protein, mouse
keywords: amacrine cell; dopamine; ganglion cell; melanopsin; retina; vision