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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

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.

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