1. THE FUNCTIONS OF THE INTRINSICALLY
PHOTOSENSITIVE RETINAL GANGLION
CELLS (ipRGCS)
By: Fatema Jivajee
Student no: 1301461
2. Overview of contents:
Intrinsically photosensitive retinal ganglion cells (ipRGCs)
iPRGCs Vs. conventional Retinal ganglion cells (RGCs)
Circadian rhythms
Circadian rhythms in the blind
Potential treatments
3. Intrinsically photosensitive retinal ganglion cells
(ipRGCs)
• The traditional visual model assumes perception of the world is done by two
types of retinal photoreceptors:
Cones (Daytime vision, perception of fine detail colour)
Rods (Dim light vision, sensitive to a wider band of wavelengths of light)
• Photosensitive cells discovered in the retina of blind mice by Clyde Keeler in
1923 and proven 8 decades later to be intrinsically photosensitive retinal ganglion
cells (ipRGCs) (Pickard & Sollars, 2012).
• ipRGCs are responsible for non-image forming visual responses to light,
including pupillary light reflexes and changes in the sleep-wake cycle (Schmidt
and Kofuji, 2009).
• An opsin-like photopigment known as melanopsin (encoded by the gene Opn4)
within the cell bodies, proximal axons and throughout the dendrites (Hattar et. Al.,
2002).
• Studies carried out on genetic mouse models revealed 5 subtypes: M1, M2, M3,
M4 and M5 ipRGCs (Schmidt et. Al., 2011).
4. iPRGCs Vs. conventional Retinal ganglion cells (RGCs)
• iPRGCs express a peptide known as pituitary adenylyl cyclase-activating
protein (PACAP) which aids in the function of its non-image forming response.
Studies have revealed a relationship between impaired PACAP signalling and
impaired circadian photoentrainment in animals (Berson et. al., 2002).
• iPRGCs expresses melanopsin, the photopigment responsible for the intrinsic
light response at short blue wavelength ∼480 nm light. Conventional RGCs do
not express any photopigment receive image-forming information from the
rods/cones and colour vision in the case of cones.
• iPRGCs have larger cell bodies with larger dendritic tree diameters as
compared to the conventional RGCs (Dacey et. al., 2005).
• Project to the suprachiamatic nuclei, lateral geniculate nucleus and the olivary
pretectal nuclei
5. 2. Pathway of ipRGCs to the brain for
non-image forming visual responses
to light
1. Pathway of conventional RGCs to the
brain in image forming visual responses
to light
6. iPRGCs Vs. conventional Retinal ganglion cells (RGCs)
The functions of M1 ipRGCs, conventional RGCS and
non-M1 ipRGCs (M2-M5). The functions of M1 ipRGCs
are the most documented due to their function in
circadian photoentrainment and pupillary light reflexes.
The collective functions of the non-M1 ipRGCs (M2-
M5) have been studies although the specialized
function of the individual ipRGC subtypes are unknown.
The conventional RGCs are related to their image-
forming visual responses.
Image from (Schmidt et. al., 2011).
7. The circadian rhythm
• The internal near 24 hour oscillator in the anterior hypothalamic
suprachiasmatic nuclei (SCN) of the brain is responsible for
regulation of circadian cycles is present
• Natural circadian cycle in humans is 24.2 to 25.5 hours
discovered by cave studies pioneered by French speleologist
Michel Siffre
• Sensory inputs ensure that the intrinsic period of the SCN
oscillator is synchronized with that of the light/dark cycle
produced by the earth’s rotation on its axis every 24 hours
• Molecular evolutionary studies reveal similarities of molecules
within the circadian clock in humans and of other distant
species
• A negative feedback loop mechanism
• ipRGCs are involved in the alignment of their circadian rhythms
with the light/dark cycles which is known as circadian
photoentrainment (Provencio et. al., 1998, 2000).
8. What are the effects on the circadian rhythms of blind
individuals who do not have the conscious perception of
light?
• Normal 24-hour circadian rhythms
• Unusual rhythms in blood pressure, heart rate and urinary excretion
• Irregular production of corticosteroid observed in the blood plasma
• Atypical melatonin rhythms
• Abnormal sleeping patterns which led to an abnormal phase of rectal temperature.
• A lowered amplitude of the excretion rates of electrolytes along with irregular excretion
rhythms of electrolytes mainly sodium, chloride and potassium ions
• Higher prevalence of sleeping disorders and disturbance of sleep (Lockley et. al., 2007).
9. Possible treatments
• Melatonin administration: although the ultimate dose and the time of
administration has not yet been determined
• Light therapy
• Light restriction
10. References
Image 1 derived from: <http://www.mhhe.com/cgi-
bin/netquiz_get.pl?qfooter=/usr/web/home/mhhe/biosci/genbio/maderbiology7/student/olc/art_quizzes/0691fq.htm&afooter=/usr/web/home/mhhe/biosci/g
enbio/maderbiology7/student/olc/art_quizzes/0691fa.htm&test=/usr/web/home/mhhe/biosci/genbio/maderbiology7/student/olc/art_quizzes/0691q.txt&ans
wers=/usr/web/home/mhhe/biosci/genbio/maderbiology7/student/olc/art_quizzes/0691a.txt>
Image 2 derived from: http://thebrain.mcgill.ca/flash/d/d_11/d_11_cr/d_11_cr_hor/d_11_cr_hor.html
BERSON, D.M., 2003. Strange vision: ganglion cells as circadian photoreceptors. Trends in neurosciences, 26(6), pp. 314-320.
DACEY, D.M., LIAO, H.-., PETERSON, B.B., ROBINSON, F.R., SMITH, V.C., POKOMY, J., YAU, K.-. and GAMLIN, P.D., 2005. Melanopsin-expressing
ganglion cells in primate retina signal colour and irradiance and project to the LGN.Nature, 433(7027), pp. 749-754.
HATTAR, S., LIAO, H.W., TAKAO, M., BERSON, D.M. and YAU, K.W., 2002. Melanopsin-containing retinal ganglion cells: architecture, projections, and
intrinsic photosensitivity. Science (New York, N.Y.), 295(5557), pp. 1065-1070.
LOCKLEY, S.W., ARENDT, J. and SKENE, D.J., 2007. Visual impairment and circadian rhythm disorders. Dialogues in clinical neuroscience, 9(3), pp.
301-314.
PICKARD, G.E. and SOLLARS, P.J., 2012. Intrinsically Photosensitive Retinal Ganglion Cells. Berlin, Heidelberg: Springer Berlin Heidelberg.
PROVENCIO, I., JIANG, G., DE GRIP, W.J., HAYES, W.P. and ROLLAG, M.D., 1998. Melanopsin: An opsin in melanophores, brain, and
eye. Proceedings of the National Academy of Sciences, 95(1), pp. 340-345.
PROVENCIO, I., RODRIGUEZ, I.R., JIANG, G., HAYES, W.P., MOREIRA, E.F. and ROLLAG, M.D., 2000. A Novel Human Opsin in the Inner Retina. The
Journal of Neuroscience, 20(2), pp. 600-605.
SCHMIDT, T.M., CHEN, S. and HATTAR, S., 2011. Intrinsically photosensitive retinal ganglion cells: many subtypes, diverse functions. Trends in
neurosciences, 34(11), pp. 572-580.
SCHMIDT, T.M. and KOFUJI, P., 2009. Functional and Morphological Differences among Intrinsically Photosensitive Retinal Ganglion Cells. The Journal
of Neuroscience, 29(2), pp. 476-482.
11. Summary of contents:
Intrinsically photosensitive retinal ganglion cells (ipRGCs)
iPRGCs Vs. conventional Retinal ganglion cells (RGCs)
Circadian rhythms
Circadian rhythms in the blind
Potential treatments
In 1923, Clyde Keeler discovered that the mice he was breeding for research had experienced a mutation that caused their eyes to lack photoreceptors – light-sensing cells located in the retina. This came as a bit of a shock, because the rodents, which should have been totally blind, reacted to light: Not only did their pupils shrink, but their bodies maintained circadian rhythms.
Similar observations were made in humans; such that light remained effective in suppressing pineal melatonin secretion and entraining the circadian clock in some people who were blind from severe loss of rods and cones
Differ greatly from rods and cones as they are much less sensitive to light, and have far less spatial resolution. Light depolarizes ipRGCs but hyperpolarizes rods and cones
M1- stratify in the outermost sublamina of the inner plexiform layer
M2- stratify in the innermost sublamina of the inner plexiform layer
M3-bistratified RGC with dendrites in both the inner and outer sublaminae
Suprachiasmatic nuclei is responsible for the circadian and melatonin responses,
Olivary pretectal nuclei is responsible for the pupillary light reflexes
a. The most prominent targets of RGC axons are the dorsal lateral geniculate nucleus (dLGN), the location through which light information travels en route to the visual cortex, and other regions involved in conventional image vision.
b. In the case of the iprgcs, there was photic activation of the suprachiasmatic nucleus (SCN), the master circadian pacemaker, suggesting that the retina was already feeding light signals into the retinohypothalamic tract (RHT).
ipRGCs and circadian rhythms are highly studied in the blind as they lack the image forming visual response that people with normal vision crucially rely upon for environmental cues such as light in the case of synchrony of their circadian rhythm. The blind therefore are mainly dependent on the ipRGCs for these environmental light cues and as there is no interference by the image forming light responses from the rods and cones that are relayed to the RGCs , the blind are a novel sample to study.
Sometimes changes in the circadian rhythm are due to nonphotic factors e.g
Timing of sleep
Carbohydrate intake
Other potential nonphotic synchronizers that include social interaction and olfactory cues
Where melatonin causes a phase delay shift (to a later time), the opposite of that is required for photoentrainment
