2. Presentation layout
• Introduction
• Physiology of the RPE/ Neural Retina
• Visual Cycle
• Phototransduction
• Information processing within the retina
• Light /Dark adaptation
2
3. RETINA
• Retina: In latin “rete” means
net like.
• It has two main components:
- sensory layer
- pigmented layer
• It is the innermost tunic of
eyeball
3
5. Light passes through most of
the retinal layers
Reaches and stimulates the
photoreceptor outer segment
discs
The neural flow then proceeds
back through the retinal
elements in the opposite
direction of the incident light
5
6. Physiology of the RPE
Absorption of scattered light
Blood retinal barrier function
Visual pigment regeneration and synthesis
Synthesis of growth factors
Maintenance of retinal adhesion
Phagocytosis
Electrical homeostasis
Repair and regeneration after injury
6
7. Absorption of light
• As a pigment layer of cells , it absorbs scattered
light to improve the optical quality.
• Light is absorbed by the melanin granule of
RPE leading to increase in temperature of the
RPE choroid complex.
• The heat is transported away by the bloodstream
in the choriocapillaris.
7
8. Retinal Pigments
• Melanin
• Contain within the cytoplasmic granules of
melanosomes
• In old age, these pigments fuse with lysosome and
break down
• Absorb stray lights and minimize scatter within the eye
• Serves as a free radical stabilizer, bind toxins and
retinotoxic drugs
8
10. Retinal Pigments
• Lipofuscin
• Accumulates gradually with age
• Derived from
- the outer segment lipids that have
been ingested and then digested by
the RPE
- membrane fragments that have
been damaged by the light or
oxidation
• Clinically seen as Drusens
10
11. Transepithelial transport
RPE constitute a monolayer of cells; cuboidal in cross
section and hexagonal when looked from above
Joined by the tight junctions ( zonulae occludens)
Block the free passage of water and ions
Equivalent to blood retinal barrier which are formed by
the capillary endothelium of intrinsic retinal vasculature.
11
12. Transport from the blood side
to the photoreceptor side
Transport from the retinal side
to the blood side
• Glucose transporters GLUT 1
and GLUT 3
• omega 3 fatty acid
• retinal
• The retina is the tissue with the
highest density of cells.
• Neuronal cells show a high
metabolic activity, results in the
production of large amount of
water and accumulation of lactic
acid
• Also additional amount of water
are moved towards the retina by
intraocular pressure from
vitreous.
• Since RPE is tight epithelium
water cannot pass through
paracellular route.
• The transport of water is driven
by an active transport of Cl-
from the retina to the blood side
12
13. CSCR (Central Serous Chorioretinopathy)
Serous detachment is not that fluid gets in ( given that a break is present in
RPE barrier) ,but that the fluid accumulates and persists (since the
powerful RPE would be expected to pump it right back)
13
15. Phagocytosis of photoreceptors outer
segments
Photoreceptors
Light
(radiant
Source)
Oxygen
(from the
choroid)
15
Free Radicals
Production
Damage Membranes
Over time
16. 16
• Everyday around 100 discs at the distal end of photoreceptors are
phagocytosed by the RPE while new discs are being synthesized
• Cell renewal process follows a cicardian rhythm : rod shed more
vigorously in the morning whereas cones shed more in the
darkness
• Within the RPE the phagocytosed disc becomes encapsulated in
vesicles called phagosomes
Merge with lysosome for digestion
Fatty acids are retained for recycling into outer segment
Waste or damaged membrane material is egested across the basal
RPE membrane
18. Age Related Maculopathy
• RPE ingests and degrades rod outer segment , as
a consequence , lipofuscein accumulates in
RPE cells with age
• Oxidative stress ( light , smoking, low level of
antioxidant vitamins ) will increase lipofusin
accumulation as well as thickening of
extracellular matrix.
18
19. Secretion
• The RPE is capable of secreting a large variety of growth
factors, cytokines or immune modulators.
• Growth factors elaborated by RPE serve not only to
modulate the behavior of RPE but also its surrounding
tissues such as choriocapillaries
• Functions:
vascular supply
permeability
growth
repair
other processes vital to retinal function
19
21. Age- related Macular Degeneration
(AMD)
• One of the cause of irreversible visual loss in
industrialized countries
• Degenerative changes in the RPE cells,
extracellular matrix and possibly
choriocapillaries leads to malnutrition of
photoreceptors and RPE cells
• Two different responses to this malnutrition lead
to form two form of advanced AMD
21
22. AMD
Atrophic Form Neovascular Type
• Characterised by
Insufficient production of
survival factors by damaged
RPE
• Leading to apoptosis of
functional complexes formed
by choriocapillaries, RPE and
photoreceptors
• RPE and possibly
photoreceptors produce
excess VEGF
• Stimulates outgrowth of new
capillaries , CNV
• Clinically antagonists of VEGF
are injected in exudative AMD,
often stabiling or even
improving vision
22
23. Retinal Adhesion
• Interphotoreceptor matrix (IPM) contain glycosaminoglycans
(GAGs) which surround rod and cones
• IPM functions:
• - physical support to the photoreceptors
• - transfer of nutrients and visual pigments
• - formation of an adhesive bond between retina and RPE
• The IPM function is largely controlled by RPE through
synthesis of matrix materials and transport proteins and also
through transport of ions and water.
23
24. OTHER MECHANISM
• Vitreous gel
• Intraocular fluid pressure
• RPE water transport
• Mechanical interdigitation
24
26. Electrical Activity In RPE
• Asymmetrical transport property of apical and basal
membrane generates transepithelial voltage(standing
potential)
• Light incident upon the photoreceptors causes the
potassium concentration of subneural retinal space falls
• Response: apical membrane of RPE and muller cell
hyperpolarizes
• Light activation of photoreceptors causes the release of
unknown messenger that causes the basal RPE
depolarization.
26
27. Repair And Regeneration
• Although of neural origin the RPE are the pluripotent tissues
• Capable of local repair and cell migration
Examples
1. Laser burns: RPE surrounding the burn begin to
divide and fill the defect to form a new BRB within
1-2 weeks.
2. Retinitis pigmentosa: RPE migrate into the
injured neural retina and comes to rest around
vessels to contribute the characteristic bone spicule
appearance
3. Macular degenerative process : vigorous RPE
response can lead to duplicated layers of RPE cells
and RPE scarring
27
28. The most important function of RPE is the
ability to heal defects
Valuable in?
• photocoagulation for macular edema and
proliferative diabetic retinopathy
• The ability of RPE cells to seal laser scars, re-establish
a degree of normal transport and avoid unnecessary
leakage of proteins into the subretinal space.
28
Dependent upon
32. PHYSIOLOGY OF THE NEURAL RETINA
80 to 110 million rods
4 to 6 million cones
Approximately 35 million bipolar cells
1.12 to 2.22 million ganglion cells
Signals from numerous photoreceptors converge at
one ganglion cell
32
34. Relatively small number of cones drive the cone
bipolar cell
Small number of cone bipolar cells drive a single
ganglion cell
In some situations, 1:1 ratio between cones and
ganglion cells
Reflecting the significant amount of detail that
the cone population can discriminate
34
36. RHODOPSIN
• Present in outer segment of Rods
• OPSIN + RETINAL= RHODOPSIN
• It is insoluble in water
• Sensitive to acid and alkalis
• Absorbs yellow wavelength of light, transmits
violet to red colour, hence appears visual purple.
36
37. Cone pigments
• 3 kinds:
• CYANOLABE : blue sensitive 435nm
• CHLOROLABE : green sensitive 535 nm
• ERYTHROLABE : red sensitive 580 nm
• Responsible for colour vision
• Cone pigments are different from Rhodopsin in
opsin portion , 11-cis retinal is same as
Rhodopsin
37
38. Colour Blindness
Normal colour vision uses all three types of light
cones correctly known as Trichromacy
People with “faulty” trichromatic vision will be
colour blind
The different anomalous conditions are :
• PROTANOMALY
• DEUTERANOMALY
• TRITANOMALY
RED-GREEN COLOUR BLIND
40. Opsin
Long helix
348 amino acids
• Loop seven times
• Determines the
wavelength absorbed by a
photoreceptor
• 11-cis-retinal, derivative of
vitamin A
40
41. Phototransduction
• It is Series of biochemical events :
• Photon of light is changed to an electrical signal
• Occurs in the photoreceptors
• Visual pigments in the photoreceptor outer segment
absorb light
• Initiates the process of vision
41
Photons captured Hyperpolarization
Release of
Neurotransmitter
44. The membrane potential
• Rods have resting membrane potential of -40mV
• Na+/K+ATPase pumps Na+ out of the cell and
K+ inside .
• K+ channels are predominant in resting state
44
45. 45
Incident Light
Change in Opsin
Configuration
Retinene1 changed to
All-trans form
α-Subunit separates
Transducin (Gα)
is activated
ACTIVATION
CASCADE
49. Bipolar Cells
• 1st order neuron in visual pathway
• Once a threshold is reached, the ganglion cell
responds and a signal is sent to higher CNS
locations
• Rod bipolars do not synapse with ganglion
cells directly but with amacrine cells
• TYPES
1. On Bipolar cells
2. Off Bipolar cells
49
50. 50
When Glu binds to the ionotropic receptor on a
bipolar dendrite
• Cation channels are opened in the cell membrane,
causing the bipolar cell to depolarize and release Glu
• This is an OFF bipolar because it is depolarized
in the dark
51. 51
When Glu binds to the metabotropic receptors on a
bipolar cell dendrite
• Decrease of cGMP occurs
• Closing cation channels in the cell membrane and
causing the bipolar cell to hyperpolarize
• Results in a decrease of glutamine release
• This is an ON bipolar because it is hyperpolarized in
the dark/ depolarized in the light
52. 52
ON or OFF designation does not imply that the bipolar
itself is responding to the light condition; only
photoreceptors do that
OFF Bipolar
• Depolarizes in
dark
• Hyperpolarize
in light
On Bipolar
• Depolarizes in
light
• Hyperpolarize
in dark
53.
54. Amacrine Cells
• Receive information at
the synapse of the
bipolar cell axons with
the ganglion cell
dendrites
• Bipolar cells project
onto both ganglion and
amacrine cells
• Negative feedback
• Reciprocal inhibition
• Works laterally
54
55. Ganglion Cell
• Electrical response of bipolar cells after modification by
the amacrine cells
• Transmit the information by means of action potential
• Two types depending upon their response upon
illumination of the centre of receptive
1. on center
2. off center
• Three groups; W, X And Y ganglions
55
56. Receptive Fields
• When light activates cells in the center of field, a given response
occurs
• When light falls on the surround , an antagonistic response
occurs
56
Arranged in a center-surround pattern
58. The center-surround configuration
allows a neuron
• To respond to a direct message
• To gather information from neighboring areas
• Provide details e.g. detection of edges
• Maximizes retinal contrast sensitivity
58
59. Seen at the level of
Bipolar cells
Ganglion cells
LGN
Striate cortex
59
60. VISUAL ADAPTATION
• Light adaptation: Retina adapting to bright light
Very quick
Merely disappearance of Dark Adaptation
60
61. Dark adaptation curve
Visual threshold falls progressively
Initial small curve
• represents the adaptation of cones
Remainder of the curve
• represents adaptation of rods
61
62. Night Blindness
• Mild cases of Vitamin A deficiency lead to a
slowing of S2 component of the dark
adaptation, yet without any alteration in the
fully dark adapted visual threshold
• Why?
Because all the bleached opsin is able to combine
with retinoid, the recombination is simply
slowed.
63. 63
• 1 minute : 10 x sensitivite
• 20 minute : 6000 x sensitive
• 40 minute : 25000 x sensitive
• When fully dark adapted, the retina is about
one lakh times more sensitive to light than
when bleached
64. Mechanism
• Visual pigment mechanism
• Other mechanisms
• - Change in pupil size
• - Neural adaptation
64
Feedback inhibition
Lies within the neuron itself
65. What are the Factors that prolong
dark adaptation ?
Vitamin A deficiency
Age related maculopathy
Anoxia
Tobacco
Anaesthesia
Opacities in the ocular media
Retinal degeneration
Myopia
65
66. • Delayed dark adaptation
occurs in diseases of rods
e.g., vitamin A deficiency &
retinitis pigmentosa
Oguchi’s disease:
• prolonged rod dark adaptation
• Despite normal rhodopsin
regeneration
• Demonstrate neural mechanism of
dark adaptation
66
67. References
Adler’s Physiology Of The Eye – 11th Edition
Anatomy And Physiology Of Eye - 2nd Edition- A. K
Khurana
Yanoff & Duker Ophthalmology - 4h Edition
Clinical Ophthalmology - 8th Edition- J. Kanski
AAO Retina and Vitreous - Section 12
AAO Fundamentals and Principles of Ophthalmology -
Section 2
67
Hypoplasia of the RPE FOLLOWING THE axial elongation reduces the melanin pigment , allowing the choroidal vessels to be seen giving it a tesselated appeareance. Commonly seen in elderly , clinically insignificant
Glucose transporters GLUT 1 and GLUT 3
w3 fatty acid
Retinal
The retina is the tissue with the highest density of cells.
Neuronal cells show a high metabolic activity, results in the production of large amount of water and accumulation of lactic acid
Also additional amount of water are moved towards the retina by intraocular pressure from vitreous.
Since RPE is tight epithelium water cannot pass through paracellular route.
The transport of water is driven by an active transport of Cl- from the retina to the blood side
the condition that causes fluid to build up underneath the center of retina
Vision starts in photo receptors outer segment with absorption of photon by chromophobe of rhodopsin
11-cis retinal which undergoes a conformational change from 11-cis retinal to all trans retinol
For absorption of next photon, rhodopsin needs replacement for all cis retinal
To maintain visual function a reisomerisation of all trans to 11-cis retinal takes place in RPE
RPE microvilli wrap closely around the tips of the outer segment .
It is seen in retinal detachment it is CLumping of pigmented cells in the anterior chamber and on corneal endothelium. Also known as “Tobacco Dust “ .
Retinitis pigmentosus :PROGRESSIVE ROD CONE DYSTROPHY
RPE migrate into the injured neural retina and comes to rest around vessels to contribute the characteristic bone spicule appearance
PROGRESSIVE CONE DYSTROPHY
Mainly cone dystrophy, but later patient may develop rod dystrophy in late life, hence overlap b/w progressive cone-rod dysfunction.
Fundus: early pigment mottling, bull’s eye macular atrophy , temporal optic atrophy , tapetal retinal reflexes ( glisering greenish golden seen)
There are several types of inherited colour blindness.
PROTANOMALY REDUCED SENSITIVITY TO RED LIGHT
DEUTAROMALY REDUCED SENSITIVITY O GREEN LIGHT
People with deuteranomaly and protanomaly are collectively known as red-green colour blind and they generally have difficulty distinguishing between reds, greens, browns and oranges. They also commonly confuse different types of blue and purple hues.
People with reduced blue sensitivity have difficulty identifying differences between blue and yellow, violet and red and blue and green. To these people the world appears as generally red, pink, black, white, grey and turquoise
TRITANOMALY REDUCED SENSITIVITY TO BLuE LIGHT
iN dark
The less negative resting membrane potential is due cGMP-gated channels as it only passes cations. (Na+ cation)
Na+ exiting the inner segment moves into the outer segment, through the open channel
Dark current / standing potential
Photoreceptor cells
Depolarized in the dark
Light hyperpolarizes and switches off these cells
Photoreceptor depolarized approximately −40 mV membrane potential
Voltage-gated Ca++ channels open
Calcium ions facilitate glutamate release into the synaptic cleft
This 'switching off' that activates the next cell and sends the signal down the neural pathway (depending on the type of cells)
Light ..decrease release of glutamine from end of the photoreceptors …no inhibition of bipolar cells …(depolarized)…increase release of excitatory transmitter facilitation of ganglion cells.
Dark …increase
Consists of the area in the visual field or the area of the retina that, when stimulated, elicits a response in a retinal neuron
All the photoreceptors and horizontal cells can influence it
Receptive field is enlarged beyond its dendritic tree
Fundus albipunctatus mutation in 11- cis retinol
ARM characterised by thickened bruch’s membrane and deposition of neural lipids
Transport of vitamin A in from the choroidal circulation is hindered, so RPE / retina becomes Vitamin A deficient, i.e there is ocular Vitamin A deficiency