Section of retina: light strikes first the ganglion cell layer, last the rods and cones
Intrinsically photosensitive retinal ganglion cells (ipRGCs), also called photosensitive retinal ganglion cells (pRGC), or melanopsin-containing retinal ganglion cells (mRGCs), are a type of neuron in the retina of the mammalian eye.
The presence of ipRGCs were first noted in 1923 when rodless, coneless
mice still responded to a light stimulus through pupil constriction,
suggesting that rods and cones are not the only light-sensitive neurons
in the retina. It wasn't until the 1980s that advancements in research
on these cells began. Recent research has shown that these retinal ganglion cells, unlike other retinal ganglion cells, are intrinsically photosensitive due to the presence of melanopsin, a light-sensitive protein. Therefore they constitute a third class of photoreceptors, in addition to rod and cone cells.
Overview
Compared to the rods and cones, the ipRGCs respond more sluggishly and signal the presence of light over the long term. They represent a very small subset (~1%) of the retinal ganglion cells.
Their functional roles are non-image-forming and fundamentally
different from those of pattern vision; they provide a stable
representation of ambient light intensity. They have at least three
primary functions:
- They play a major role in synchronizing circadian rhythms to the 24-hour light/dark cycle, providing primarily length-of-day and length-of-night information. They send light information via the retinohypothalamic tract (RHT) directly to the circadian pacemaker of the brain, the suprachiasmatic nucleus of the hypothalamus. The physiological properties of these ganglion cells match known properties of the daily light entrainment (synchronization) mechanism regulating circadian rhythms. In addition, ipRGCs could also influence peripheral tissues such as the hair follicle regeneration through SCN-sympathetic nerve circuit.
- Photosensitive ganglion cells innervate other brain targets, such as the center of pupillary control, the olivary pretectal nucleus of the midbrain. They contribute to the regulation of pupil size and other behavioral responses to ambient lighting conditions.
- They contribute to photic regulation and acute photic suppression of release of the hormone melatonin.
- In rats, they play some role in conscious visual perception, including perception of regular gratings, light levels, and spatial information.
An
ipRGC, shown here as a complied image of the retina from proximal inner
nuclear layer to the ganglion cell layer with fluorescent labeling of
melanopsin
Photoreceptive ganglion cells have been isolated in humans, where, in
addition to regulating the circadian rhythm, they have been shown to
mediate a degree of light recognition in rodless, coneless subjects
suffering with disorders of rod and cone photoreceptors. Work by Farhan H. Zaidi and colleagues showed that photoreceptive ganglion cells may have some visual function in humans.
The photopigment of photoreceptive ganglion cells, melanopsin, is
excited by light mainly in the blue portion of the visible spectrum
(absorption peaks at ~480 nanometers). The phototransduction mechanism in these cells is not fully understood, but seems likely to resemble that in invertebrate rhabdomeric
photoreceptors. In addition to responding directly to light, these
cells may receive excitatory and inhibitory influences from rods and
cones by way of synaptic connections in the retina.
The axons from these ganglia innervate regions of the brain related to object recognition, including the superior colliculus and dorsal lateral geniculate nucleus.
Structure
ipRGC receptor
Melanopsin structure
These photoreceptor cells project both throughout the retina and into
the brain. They contain the photopigment melanopsin in varying
quantities along the cell membrane, including on the axons up to the
optic disc, the soma, and dendrites of the cell. ipRGCs contain membrane receptors for the neurotransmitters glutamate, glycine, and GABA.
Photosensitive ganglion cells respond to light by depolarizing, thus
increasing the rate at which they fire nerve impulses, which is opposite
to that of other photoreceptor cells, which hyperpolarize in response
to light.
Results of studies in mice suggest that the axons of ipRGCs are unmyelinated.
Melanopsin
Unlike other photoreceptor pigments, melanopsin
has the ability to act as both the excitable photopigment and as a
photoisomerase. Instead of requiring additional cells to revert between
the two isoforms, from all-trans-retinal back into 11-cis-retinal before it can undergo another phototransduction, like the photoreceptor cones, which rely on Müller cells and retinal pigment epithelium cells for this conversion, melanopsin is able to isomerize all-trans-retinal into 11-cis-retinal when stimulated with light without help from additional cells. The two isoforms of melanopsin differ in their spectral sensitivity, for the 11-cis-retinal isoform is more responsive to shorter wavelengths of light, while the all-trans isoform is more responsive to longer wavelengths of light.
Synaptic inputs and outputs
Synaptic inputs and outputs of ipRGCs and their corresponding location in the brain
Inputs
ipRGCs are both pre- and postsynaptic to dopaminergic amacrine cells
(DA cells) via reciprocal synapses, with ipRGCs sending excitatory
signals to the DA cells, and the DA cells sending inhibitory signals to
the ipRGCs. These inhibitory signals are mediated through GABA, which is co-released from the DA cells along with dopamine.
Dopamine has functions in the light-adaptation process by up-regulating
melanopsin transcription in ipRGCs and thus increasing the
photoreceptor's sensitivity.
In parallel with the DA amacrine cell inhibition,
somatostatin-releasing amacrine cells, themselves inhibited by DA
amacrine cells, inhibit ipRGCs. Other synaptic inputs to ipRGC dendrites include cone bipolar cells and rod bipolar cells.
Outputs
One
postsynaptic target of ipRGCs is the suprachiasmatic nucleus (SCN) of
the hypothalamus, which serves as the circadian clock in an organism.
ipRGCs release both pituitary adenylyl cyclase-activating protein
(PACAP) and glutamate onto the SCN via a monosynaptic connection called the retinohypothalamic tract (RHT). Glutamate has an excitatory effect on SCN neurons, and PACAP appears to enhance the effects of glutamate in the hypothalamus.
Other post synaptic targets of ipRGCs include: the
intergenticulate leaflet (IGL), a cluster of neurons located in the
thalamus, which play a role in circadian entrainment; the olivary
pretectal nucleus (OPN), a cluster of neurons in the midbrain that
controls the pupillary light reflex; the ventrolateral preoptic nucleus
(VLPO), located in the hypothalamus and is a control center for sleep; as well as to the amygdala.
Function
Pupillary light reflex
Inputs and outputs to ipRGCs involved in the pupillary light reflex
Using various photoreceptor knockout mice, researchers have
identified the role of ipRGCs in both the transient and sustained
signaling of the pupillary light reflex (PLR). Transient PLR occurs at dim to moderate light intensities and is a result of phototransduction occurring in rod cells, which provide synaptic input onto ipRGCs, which in turn relay the information to the olivary pretectal nucleus in the midbrain. The neurotransmitter involved in the relay of information to the midbrain from the ipRGCs in the transient PLR is glutamate.
At brighter light intensities the sustained PLR occurs, which involves
both phototransduction of the rod providing input to the ipRGCs and
phototransduction of the ipRGCs themselves via melanopsin. Researchers
have suggested that the role of melanopsin in the sustained PLR is due
to its lack of adaptation to light stimuli in contrast to rod cells,
which exhibit adaptation. The sustained PLR is maintained by PACAP release from ipRGCs in a pulsatile manner.
Possible role in conscious sight
Experiments
with rodless, coneless humans allowed another possible role for the
receptor to be studied. In 2007, a new role was found for the
photoreceptive ganglion cell. Zaidi and colleagues showed that in humans
the retinal ganglion cell photoreceptor contributes to conscious sight as well as to non-image-forming functions like circadian rhythms, behaviour and pupillary reactions.[6] Since these cells respond mostly to blue light, it has been suggested that they have a role in mesopic vision[citation needed] and that the old theory of a purely duplex retina
with rod (dark) and cone (light) light vision was simplistic. Zaidi and
colleagues' work with rodless, coneless human subjects hence has also
opened the door into image-forming (visual) roles for the ganglion cell
photoreceptor.
The discovery that there are parallel pathways for vision was
made: one classic rod- and cone-based arising from the outer retina, the
other a rudimentary visual brightness detector arising from the inner
retina. The latter seems to be activated by light before the former.[6]
Classic photoreceptors also feed into the novel photoreceptor system,
and colour constancy may be an important role as suggested by Foster[citation needed].
It has been suggested by the authors of the rodless, coneless
human model that the receptor could be instrumental in understanding
many diseases, including major causes of blindness worldwide such as glaucoma, a disease which affects ganglion cells.
In other mammals, photosensitive ganglia have proven to have a
genuine role in conscious vision. Tests conducted by Jennifer Ecker et
al. found that rats lacking rods and cones were able to learn to swim
toward sequences of vertical bars rather than an equally luminescent
gray screen.[5]
Violet-to-blue light
Most work suggests that the peak spectral sensitivity of the receptor is between 460 and 484 nm. Lockley et al. in 2003[16]
showed that 460 nm (blue) wavelengths of light suppress melatonin twice
as much as 555 nm (green) light, the peak sensitivity of the photopic
visual system. In work by Zaidi, Lockley and co-authors using a rodless,
coneless human, it was found that a very intense 481 nm stimulus led to
some conscious light perception, meaning that some rudimentary vision
was realized.[6]
Discovery
In 1923, Clyde E. Keeler observed that the pupils in the eyes of blind mice he had accidentally bred still responded to light.[17] The ability of the rodless, coneless mice to retain a pupillary light reflex was suggestive of an additional photoreceptor cell.[8]
In the 1980s, research in rod- and cone-deficient rats showed
regulation of dopamine in the retina, a known neuromodulator for light
adaptation and photoentrainment.[1]
Research continued in 1991, when Russell G. Foster and colleagues, including Ignacio Provencio, showed that rods and cones were not necessary for photoentrainment, the visual drive of the circadian rhythm, nor for the regulation of melatonin secretion from the pineal gland, via rod- and cone-knockout mice.[18][8] Later work by Provencio and colleagues showed that this photoresponse was mediated by the photopigment melanopsin, present in the ganglion cell layer of the retina.[19]
The photoreceptors were identified in 2002 by Samer Hattar,
David Berson and colleagues, where they were shown to be melanopsin
expressing ganglion cells that possessed an intrinsic light response and
projected to a number of brain areas involved in non-image-forming
vision.[20][21]
In 2005, Panda, Melyan, Qiu, and colleagues demonstrated that the
melanopsin photopigment was the phototransduction pigment in ganglion
cells.[22][23]
Dennis Dacey and colleagues showed in a species of Old World monkey
that giant ganglion cells expressing melanopsin projected to the lateral geniculate nucleus (LGN).[24][3] Previously only projections to the midbrain (pre-tectal nucleus) and hypothalamus (supra-chiasmatic nuclei, SCN) had been shown. However, a visual role for the receptor was still unsuspected and unproven.
Research
Research in humans
Attempts
were made to hunt down the receptor in humans, but humans posed special
challenges and demanded a new model. Unlike in other animals,
researchers could not ethically induce rod and cone loss either
genetically or with chemicals so as to directly study the ganglion
cells. For many years, only inferences could be drawn about the receptor
in humans, though these were at times pertinent.
In 2007, Zaidi and colleagues published their work on rodless,
coneless humans, showing that these people retain normal responses to
nonvisual effects of light.
The identity of the non-rod, non-cone photoreceptor in humans was found
to be a ganglion cell in the inner retina as shown previously in
rodless, coneless models in some other mammals. The work was done using
patients with rare diseases that wiped out classic rod and cone
photoreceptor function but preserved ganglion cell function.
Despite having no rods or cones, the patients continued to exhibit
circadian photoentrainment, circadian behavioural patterns, melatonin
suppression, and pupil reactions, with peak spectral sensitivities to
environmental and experimental light that match the melanopsin
photopigment. Their brains could also associate vision with light of
this frequency. Clinicians and scientists are now seeking to understand
the new receptor's role in human diseases and blindness.
