Synaptic inputs to retinal ganglion cells that set the circadian clock

Eur J Neurosci. 2006 Aug;24(4):1117-23. doi: 10.1111/j.1460-9568.2006.04999.x.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bicuculline / metabolism
  • Biological Clocks / physiology*
  • Circadian Rhythm / physiology*
  • Excitatory Amino Acid Antagonists / metabolism
  • GABA Antagonists / metabolism
  • Glycine Agents / metabolism
  • Kynurenic Acid / metabolism
  • Light
  • Neural Pathways* / metabolism
  • Neural Pathways* / physiology
  • Patch-Clamp Techniques
  • Quinoxalines / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA / metabolism
  • Receptors, Glutamate / metabolism
  • Retinal Ganglion Cells / cytology
  • Retinal Ganglion Cells / metabolism*
  • Rod Opsins / metabolism
  • Strychnine / metabolism
  • Synapses / metabolism*
  • Synaptic Transmission / physiology
  • Tetrodotoxin / metabolism

Substances

  • Excitatory Amino Acid Antagonists
  • GABA Antagonists
  • Glycine Agents
  • Quinoxalines
  • Receptors, GABA
  • Receptors, Glutamate
  • Rod Opsins
  • melanopsin
  • Tetrodotoxin
  • FG 9041
  • Kynurenic Acid
  • Strychnine
  • Bicuculline