title: Synaptic inputs to retinal ganglion cells that set the circadian clock.
abstract: Melanopsin-containing retinal ganglion cells (RGCs) project to the suprachiasmatic nuclei (SCN) and mediate photoentrainment of the circadian system. Melanopsin is a novel retinal-based photopigment that renders these cells intrinsically photosensitive (ip). Although genetic ablation of melanopsin abolishes the intrinsic light response, it has a surprisingly minor effect on circadian photoentrainment. This and other non-visual responses to light are lost only when the melanopsin deficiency is coupled with mutations that disable classical rod and cone photoreceptors, suggesting that melanopsin-containing RGCs also receive rod- and cone-driven synaptic inputs. Using whole-cell patch-clamp recording, we demonstrate that light triggers synaptic currents in ipRGCs via activation of ionotropic glutamate and gamma-aminobutyric acid (GABA) receptors. Miniature postsynaptic currents (mPSCs) were clearly observed in ipRGCs, although they were less robust and were seen less frequently than those seen in non-ip cells. Pharmacological treatments revealed that the majority of ipRGCs receive excitatory glutamatergic inputs that were blocked by DNQX and/or kynurenic acid, as well as inhibitory GABAergic inputs that were blocked by bicuculline. Other ipRGCs received either glutamatergic or GABAergic inputs nearly exclusively. Although strychnine (Strych)-sensitive mPSCs were evident on many non-ipRGCs, indicating the presence of glycinergic inputs, we saw no evidence of Strych-sensitive events in ipRGCs. Based on these results, it is clear that SCN-projecting RGCs can respond to light both via an intrinsic melanopsin-based signaling cascade and via a synaptic pathway driven by classical rod and/or cone photoreceptors. It remains to be determined how the ipRGCs integrate these temporally distinct inputs to generate the signals that mediate circadian photoentrainment and other non-visual responses to light.
authors.affiliation: Neurological Sciences Institute, Oregon Health and Science University, Beaverton, OR 97006, USA.
authors.forename: Jorge Alberto
authors.initials: JA
authors.lastname: Perez-Leon
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Warren
authors.forename: Charles N
authors.initials: CN
authors.lastname: Allen
authors.forename: David W
authors.initials: DW
authors.lastname: Robinson
authors.forename: R Lane
authors.initials: RL
authors.lastname: Brown
mesh_terms: D000818:Animals; D001640:Bicuculline / Q000378:metabolism; D001683:Biological Clocks / Q000502:physiology*; D002940:Circadian Rhythm / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism; D018756:GABA Antagonists / Q000378:metabolism; D018684:Glycine Agents / Q000378:metabolism; D007736:Kynurenic Acid / Q000378:metabolism; D008027:Light; D009434:Neural Pathways / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D011810:Quinoxalines / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000378:metabolism*; D017299:Rod Opsins / Q000378:metabolism; D013331:Strychnine / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D013779:Tetrodotoxin / Q000378:metabolism; D000099210:Melanopsin
chemical_list: D001640:Bicuculline; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D018684:Glycine Agents; D007736:Kynurenic Acid; D011810:Quinoxalines; D018079:Receptors, GABA; D017470:Receptors, Glutamate; D017299:Rod Opsins; D013331:Strychnine; D013779:Tetrodotoxin; D000099210:Melanopsin; C056723:FG 9041