Retinal Synaptogenesis in Mammals

1. Retinal Synaptogenesis in Mammals Jon A. Wagnon

2. The Human Eye

3. Cross-section of the Eye

4. Cross-section of the Fovea

5. Beginning of Synaptogenesis • Neuron contacts target cell • Synapse formation begins

6. 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

7. 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

8. Fovea Formation • Fetal Day (fd) 55 in Macaca • Fetal Week (fw) 11 in Humans

9. Synaptic Formation in the Inner Retina • Tridiated Thymadine experiments show that all neurons and Müller cells are post mitotic and formed between fd36-60 • Morphological differential begins after mitosis ends

10. 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)

11. 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

12. 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

13. Synaptic Formation in the Outer Retina (cont.) • In humans • cone synapses: fw12 • rod synapses: fw18

14. Synaptic Formation in the Outer Retina (cont.) • Opsin formation follows synaptogenesis • humans: 2 months later • monkey: 2 weeks later

15. Synaptic Development • Rates and times of development change with age

16. 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

17. 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

18. 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)

19. Ribbon Synapses • Detected in the periphery at fd99 • In cone-dominated areas, develop before conventional synapses • In species with are entirely cone-dominated (e.g. tree shrew, chick), develop before conventional synapses • Ribbon synapse of the OPL appear prior to those of the IPL

20. 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)

21. 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)

22. Ribbon Synapses (cont.) • Ribbon terminals containing glycogenlike granules are concentrated in the outer half of the IPL

23. 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

24. 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

25. Conventional Synapses (cont.) • Conventional Synapses band at varying levels of the IPL depending on the species

26. 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

27. 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