Map formation

What’s really happening in the R-T system?
1. Note that, as Sperry predicted, the retina expresses a counter gradient of the receptor (EphA3). Why is this?
  1. 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.
    1. For example, growth cones may grow into the tectum randomly and continue to grow until they hit a specific ‘Stop’ signal.
      1. 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
      2. Positional info from ‘Stop’ signal?
Ephrin A2/A5 double mutant mice fail to make topographic maps
1. In rodents (mammals):
  1. Initial growth of all fibres extends throughout the tectum
  2. Subsequently, axon branching and synaptogenesis occur. It is this that is sensitive to the ephrin gradient.
  3. There appears to be competition between the axons for synaptic partners - involving electrical activity - so that weaker synapses (and their axons) get eliminated.
  4. However, if T axons have no competitive disadvantage (ie when ephrins are missing), then they can compete throughout the tectum for synapses
2. Electrical activity can modulate  responses to guidance cues
  1. 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
  2. Electrical activity modulates Ca2+ & cAMP
    1. cGMP also involved
      1. See paper and ppt for more detail
  3. Electric activity acts in part through neurotrophins
Refinement of connections is activity dependent (or Weiss was kinda right after all!)
1. 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.
  1. At later stages find that some of these contacts are lost and the map becomes more precise.
    1. This refinement depends on activity and on competition between axons.
      1. You have seen this before in your lectures on the formation of ocular dominance columns in the visual cortex:
2. Cells that fire together, wire together
  1. 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
    1. But what is happening in the embryonic tectum (superior colliculus) where mapping takes place before the animal encounters any light?
      1. 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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	Created by Kristi Brogden about 11 years ago