Retinal Synaptogenesis in
Mammals
Jon A. Wagnon
The Human Eye
Cross-section of the Eye
Cross-section of the Fovea
Beginning of Synaptogenesis
Neuron contacts target cell
 Synapse formation begins

Macaque Monkey
Genus Macaca
 Common research subject
 Similar eye formation to Humans
 165 to 175 days gestation (humans are
approximately 40 weeks)
 Slow gestation allows for greater
resolution of development

Macaque Monkey (cont.)

Retinal is cone dense at the fovea and
rod dense at the periphery, therefore
development of rods and cones can be
examined separately
Fovea Formation
Fetal Day (fd) 55 in Macaca
 Fetal Week (fw) 11 in Humans

Synaptic Formation in
the Inner Retina
Tridiated Thymadine experiments show
that all neurons and Müller cells are
post mitotic and formed between fd3660
 Morphological differential begins after
mitosis ends

Synaptic Formation in the Inner
Retina (cont.)
Early formation of the Inner Plexiform
Layer (IPL) begins between fd55-85
 Between fd85-132 IPL becomes more
compact
 Number of membrane junctions not
associated with vesicles drops with time
 No synapses in periphery until fd55-78
 Eye opening does not cue to stop
synaptogenesis (Fisher, 1979)

Synaptic Formation in the Inner
Retina (cont.)

There are three phases of IPL
synaptogenesis in mouse (Fisher, 1979b)
1. Day 3 to 10
– conventional synapses are produced
2. Day 11 to 15
– ribbon synapses are produced and conventional
synapse production increases
3. Day 15
– sharp reduction in the rate of ribbon and
conventional synapse production
Synaptic Formation in the Outer
Retina
Outer Plexiform Layer (OPL)
 Can be distinguished shortly before
ribbon formation
 Cone synapses develop before rod
synapses
 Development begins at fd60-65
 OPL synapses appear after IPL
synapses

Synaptic Formation in the Outer
Retina (cont.)

In humans
– cone synapses: fw12
– rod synapses: fw18
Synaptic Formation in the Outer
Retina (cont.)

Opsin formation follows
synaptogenesis
– humans: 2 months later
– monkey: 2 weeks later
Synaptic Development

Rates and times
of development
change with
age
Synapses

Ribbon synapse:
– contains a “ribbon”
– the ribbon may appear floating or following
an axon
– associated only with bipolar cells

Conventional synapse:
– associated with bipolar, amacrine, and
ganglion cells
Process of Synaptogenesis
1. Patches of dense filamentous membrane first appear
on the dendrites of ganglion (G) cells
2. Membrane densities on ganglion cell dendrites then
become opposed to amacrine (A) cell processes still
lacking their own membrane densities and vesicles
3. A cell processes acquire membrane specializations
associated with vesciles at the sites apposing G cell
dendrites
Process of Synaptogenesis
4. Pairs of A cell processes form AA subtypes of
conventional synapses
5. Monad ribbon synapses are established between
bipolar (B) and G or A cell processes
6. Dyad ribbon synapses (B GG; B  GA; B  AA)
are formed
7. Processes of some A cells form a feedback circuit
with B cell axons (A  B)
Ribbon Synapses
Detected in the periphery at fd99
 In cone-dominated areas, develop
before conventional synapses
 In species with are entirely conedominated (e.g. tree shrew, chick),
develop before conventional synapses
 Ribbon synapse of the OPL appear prior
to those of the IPL

Ribbon Synapses (cont.)
Ribbons of the OPL are produced with
no centro-peripheral gradient (Maslim
 Plateau at a density of 5.5/100m2
 In humans ribbons are distributed fairly
evenly throughout with the slight
suggestion of four broadly overlapping
bands (Koontz & Hendrickson, 1987)

Ribbon Synapses (cont.)
Most ribbons connect to only one
postsynaptic cell, either amacrine or
ganglionic
 There are significantly more ribbons
connecting bipolar (B) to ganglion (G)
in the fovea (91%) than in the
periphery (66%) suggesting that there
is more amacrine cell processing in the
periphery (Koontz & Hendrickson, 1987)

Ribbon Synapses (cont.)

Ribbon terminals
containing
glycogenlike
granules are
concentrated in the
outer half of the
IPL
Conventional Synapses
Sharp increase beginning at fd88
 Detected in the periphery at fd78
 Result from the aggregation of synaptic
vesicles on one side of junctions the
first existed as symmetrical membrane
densities without vesicles
 In rod-dominated areas, develop before
ribbon synapses

Conventional Synapses (cont.)
In species with no cone-dominated
areas (e.g. ferret, mouse, rabbit, rat,
guinea pig, cat) develop before ribbon
synapses
 Continued rise until after birth
 Dark rearing leads to an increase in
conventional synapses (Fisher, 1979a)
 Plateau at 15/100 m2

Conventional Synapses (cont.)

Conventional Synapses band at varying
levels of the IPL depending on the species
Synaptic Formation Related to
IPL depth

Synaptogenesis begins in the outer IPL
– may be related to the length that the axon
needs to grow
– OFF bipolar cells may form before ON cells
giving spatial and temporal dominance
Conclusions
Bipolar cells produce ribbon synapses
 Amicrine, Ganglion, and Bipolar cells
produce conventional synapses
 The type of photoreceptor dominance
determines synaptic development
 Synaptogenesis precedes opsin
formation
