The ‘Third’ Photoreceptor System of the Eye – Photosensitive Retinal Ganglion Cells

European Ophthalmic Review, 2009,2(1):84-6 DOI:
Received: February 14, 2011 Accepted February 14, 2011 Citation European Ophthalmic Review, 2009,2(1):84-6 DOI:

Until recently, it seemed inconceivable to most vision researchers and ophthalmologists alike that there could be an unrecognised class of photoreceptor within the eye. After all, the eye was the best understood part of the central nervous system. One hundred and fifty years of intensive research had explained how we see: photons are detected by the rods and cones and their graded potentials are assembled into a crude image by the inner retina, followed by advanced visual processing in the brain. This depiction of vision left no room for an additional class of photoreceptor.

However, this conventional view of retinal organisation has now been overturned. We now appreciate that the rods and cones are not the only photosensory neurons of the eye. This discovery has its origins in attempts to understand how endogenous 24-hour body clocks (circadian clocks) are regulated by light, and this is where this article will start. However, this third class of ocular photoreceptor does much more than regulate the body clock, and its contribution to a range of light detection tasks should now be factored into all assessments of clinical blindness.

Light gives both a spatial and a temporal dimension to our world. Most organisms possess an endogenous 24-hour circadian timing system that ‘fine-tunes’ physiology and behaviour to the varying demands of the day–night cycle. However, such a temporal programme is useful only if biological time remains synchronised to the solar day. The behavioural and physiological disruption we experience during ‘jet-lag’ illustrates the importance of the synchronised circadian system.

Most organisms, including humans, have evolved to use the dawn/dusk light transition as the main zeitgeber (time-giver) to adjust circadian time to local time, a process termed photoentrainment. In mammals, the master circadian pacemaker is located within small paired nuclei of the anterior hypothalamus called the suprachiasmatic nuclei (SCN), and receives a direct retinal projection via the retinohypothalamic tract. Eye loss in mammals blocks photoentrainment. Therefore, mammalian eyes perform two quite different sensory tasks: their familiar function is to collect and process light to generate an image of the world, while their less wellrecognised role is to provide measures of environmental irradiance over the period of dawn and dusk to facilitate photoentrainment. Such divergent responses to light were difficult to reconcile within the known physiology of the rods and cones, which integrate photons over extremely short time periods.1

In the early 1990s, mice homozygous for gene defects, e.g. retinal degeneration (rd), and lacking any visual responses to light were examined to determine the impact of rod/cone loss on photoentrainment. Remarkably, rd/rd mice lacking functional rods and most cones showed normal circadian responses to light.2 These and a host of subsequent experiments, including studies in humans with genetic defects of the eye,3,4 showed that the processing of light information by the circadian and classic visual systems must be different, and raised the possibility that the eye may contain an additional non-rod, noncone photoreceptor. This was a supposition that was greeted with derision by referees and funding bodies alike, based largely on the assumption that only a small number of rods and/or cones were necessary for normal photoentrainment of the clock. To test this assumption, a mouse was engineered in which all rods and cones were ablated (rd/rd cl). Such genetic lesions had little effect on circadian responses to light, although loss of the eyes completely abolished this capacity.5,6 The rd/rd cl mouse model also proved invaluable in showing that a range of other irradiance detection tasks do not require the rods and cones.

  1. Foster RG, Helfrich-Forster C, The regulation of circadian clocks by light in fruitflies and mice, Philos Trans R Soc Lond B Biol Sci, 2001;356:1779–89.
  2. Foster RG, Provencio I, Hudson D, et al., Circadian photoreception in the retinally degenerate mouse (rd/rd), J Comp Physiol, 1991;169:39–50./li>
  3. David-Gray ZK, Janssen JW, DeGrip WJ, et al., Light detection in a ‘blind’ mammal, Nat Neurosci, 1998;1:655–6./li>
  4. Czeisler CA, Shanahan TL, Klerman EB, et al., Suppression of melatonin secretion in some blind patients by exposure to bright light, N Engl J Med, 1995;332:6–11./li>
  5. Freedman MS, Lucas RJ, Soni B, et al., Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors, Science, 1999;284:502–4./li>
  6. Lucas RJ, Freedman MS, Munoz M, et al., Regulation of the mammalian pineal by non-rod, non-cone, ocular photoreceptors, Science, 1999;284,505–7./li>
  7. Whiteley SJ, Young MJ, Litchfield TM,et al., Changes in the pupillary light reflex of pigmented royal college of surgeons rats with age, Exp Eye Res, 1998;66:719–30./li>
  8. Lucas RJ, Douglas RH, Foster RG, Characterization of an ocular photopigment capable of driving pupillary constriction in mice, Nat Neurosci, 2001;4:621–6./li>
  9. Provencio I, Cooper HM, Foster RG, Retinal projections in mice with inherited retinal degeneration: implications for circadian photoentrainment, J Comp Neurol, 1998;395:417–39./li>
  10. Berson DM, Dunn FA, Takao M, Phototransduction by retinal ganglion cells that set the circadian clock, Science, 2002;295: 1070–73./li>
  11. Sekaran S, Foster RG, Lucas RJ, Hankins MW, Calcium imaging reveals a network of intrinsically light-sensitive inner-retinal neurons, Curr Biol, 2003;13:1290–98./li>
  12. Peirson SN, Thompson S, Hankins MW, Foster RG, Mammalian photoentrainment: results, methods, and approaches, Methods Enzymol, 2005;393:697–726./li>
  13. Hattar S, Lucas RJ, Mrosovsky N,et al., Melanopsin and rodcone photoreceptive systems account for all major accessory visual functions in mice, Nature, 2003;424:75–81./li>
  14. Dacey DM, Liao HW, Peterson BB, et al., Melanopsin-expressing ganglion cells in primate retina signal colour and irradiance and project to the LGN, Nature, 2005;433:749–54./li>
  15. Hankins MW, Lucas RJ, The primary visual pathway in humans is regulated according to long-term light exposure through the action of a non-classical photopigment, Curr Biol, 2002;12: 191–8./li>
  16. Provencio I, Jiang G, DeGrip WJ, et al., Melanopsin: An opsin in melanophores, brain and eye, Proc Natl Acad Sci U S A, 1998; 95:340–45./li>
  17. Bellingham J, Whitmore D, Philp AR, et al., Zebrafish melanopsin: isolation, tissue localisation and phylogenetic position, Brain Res Mol Brain Res, 2002;107:128–36./li>
  18. Provencio I, Rodriguez IR, Jiang G, et al., A novel human opsin in the inner retina, J Neurosci, 2000;20:600–605./li>
  19. Melyan Z, Tarttelin EE, Bellingham J, et al., Addition of human melanopsin renders mammalian cells photoresponsive, Nature, 2005; 33:741–45./li>
  20. Qiu X, Kumbalasiri T, Carlson SM, et al., Induction of photosensitivity by heterologous expression of melanopsin, Nature, 2005;433:745–9./li>
  21. Panda S, Provencio I, Tu DC, et al., Melanopsin Is Required for Non-Image-Forming Photic Responses in Blind Mice, Science, 2003;301(5632):525–7./li>
  22. Peirson S, Foster RG, Melanopsin: another way of signaling light, Neuron, 2006;49:331–9./li>
  23. Peirson SN, Oster H, Jones SL, et al., Microarray analysis and functional genomics identify novel components of melanopsin signaling, Curr Biol, 2007;17:1363–72./li>
  24. Sekaran S, Lall GS, Ralphs KL, et al., 2-Aminoethoxydiphenylborane is an acute inhibitor of directly photosensitive retinal ganglion cell activity in vitro and in vivo, J Neurosci, 2007;27: 3981–6./li>
  25. Hankins MW, Peirson SN, Foster RG, Melanopsin: an exciting photopigment, Trends Neurosci, 2008;31:27–36./li>
  26. Zaidi FH, Hull JT, Peirson SN, et al., Short-wavelength light sensitivity of circadian, pupillary, and visual awareness in humans lacking an outer retina, Curr Biol, 2007;17:2122–8./li>
  27. Foster RG, Wulff K, The rhythm of rest and excess, Nat Rev Neurosci, 2005;6:407–14./li>
  28. Lockley SW, Skene DJ, James K, et al., Melatonin administration can entrain the free-running circadian system of blind subjects, J Endocrinol, 2000;164:R1–R6./li>
  29. Sack RL, Brandes RW, Kendall AR, Lewy AJ, Entrainment of free-running circadian rhythms by melatonin in blind people, N Engl J Med, 2000;343:1070–77.