Map formation

Map formation

1. What’s really happening in the R-T system?

   • Note that, as Sperry predicted, the retina expresses a counter gradient of the receptor (EphA3). Why is this?
     • Although we have considered this gradient to be guiding, it is possible to conceive that the Eph-Ephrin system is only providing positional information (Sperry’s “Latitude and Longitude”), not guiding information.
       • For example, growth cones may grow into the tectum randomly and continue to grow until they hit a specific ‘Stop’ signal.
         • This signal might be a specific level of Eph receptor activation….
           • High density of receptor on temporal growth cones ensures enough signal to stop even when ligand at low density:
           • However, for more nasal growth cones, the lower density of receptor on their surface means that only when the ligand density is higher will enough signal be generated:
           • However
             • The stripe assay suggests an all or nothing, not graded response
             • And, in vitro assays suggest ephrins repel axons, not merely stop them….
           • A graded transition from growth promotion to inhibition
             • Relative outgrowth compared to growth on no (0%) ephrinA2
               • Clearly indicates that Ephrins are growth promoting at lower and inhibitory at higher ephrin concentrations
                 • Final position is where inhibition = promotion
                   • Varies according to position of origin in retina
             • See ppt for more detail
         • Positional info from ‘Stop’ signal?

2. Ephrin A2/A5 double mutant mice fail to make topographic maps

   • In rodents (mammals):
     • Initial growth of all fibres extends throughout the tectum
     • Subsequently, axon branching and synaptogenesis occur. It is this that is sensitive to the ephrin gradient.
     • There appears to be competition between the axons for synaptic partners - involving electrical activity - so that weaker synapses (and their axons) get eliminated.
     • However, if T axons have no competitive disadvantage (ie when ephrins are missing), then they can compete throughout the tectum for synapses
   • Electrical activity can modulate 
responses to guidance cues
     • Ming et al (2001. Neuron 29: 441-52) demonstrate that electrical stimulation can enhance (in the case of netrin) or reverse (in the case of MAG) the response to guidance cues
     • Electrical activity modulates Ca2+ & cAMP
       • cGMP also involved
         • See paper and ppt for more detail
     • Electric activity acts in part through neurotrophins

3. Refinement of connections is activity dependent
(or Weiss was kinda right after all!)

   • Even in “lower” vertebrates (chick/frog) where the initial map in the tectum is topographic, it is still rather coarse-grained and axons from neighbouring cells make contacts over large, overlapping areas of the tectum.
     • At later stages find that some of these contacts are lost and the map becomes more precise.
       • This refinement depends on activity and on competition between axons.
         • You have seen this before in your lectures on the formation of ocular dominance columns in the visual cortex:
   • Cells that fire together, wire together
     • The mechanism of synapse elimination involves the localised release of neurotrophic factors which is thought to be enhanced when two cells fire at the same time
       • But what is happening in the embryonic tectum (superior colliculus) where mapping takes place before the animal encounters any light?
         • Embryonic retina is spontaneously active
           • In mammals ephrins work together with electrical activity (and other survival factors) to create the topographic map
             • Tectal mapping occurs before birth in mammals, so where does the electrical activity come from? (No light?!)
             • Interestingly, the retina becomes spontaneously active as axons reach the tectum
               • See video on ppt - transient increases in intracellular calcium
               • Therefore, could be that Hebbian principles are already operating (as in ocular dominance columns)
                 • Consistent with this, treatment with the sodium channel blocker, tetrodotoxin (TTX), which blocks action potentials, blocks map refinement
                   • Can show this also by blocking nAChRs genetically….

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