Synaptic inputs to retinal ganglion cells that set the circadian clock

Aug 26, 2006The European journal of neuroscience

Nerve signals to eye cells that control the body’s daily clock

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Abstract

Melanopsin-containing retinal ganglion cells (RGCs) exhibit both intrinsic light sensitivity and synaptic responses to other photoreceptor inputs.

Genetic removal of melanopsin significantly diminishes intrinsic light responses but has a minor impact on circadian photoentrainment.
Melanopsin-containing RGCs receive synaptic inputs from rod and cone photoreceptors, indicating a dependency on these classical photoreceptors for full functionality.
Light exposure triggers synaptic currents in intrinsically photosensitive RGCs through the activation of glutamate and GABA receptors.
Miniature postsynaptic currents in intrinsically photosensitive RGCs are less frequent and robust compared to those in non-intrinsically photosensitive cells.
Pharmacological analysis shows that most intrinsically photosensitive RGCs receive both excitatory and inhibitory synaptic inputs, while some receive predominantly one type.

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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.

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Synaptic inputs to retinal ganglion cells that set the circadian clock

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