In a normal animal the retinotectal map is initially fuzzy and imprecise: the sys- tem of matching markers we have just described is enough to define the broad layout of the map, but not sufficient to specify its fine details. Studies in frogs and fish show that each retinal axon at first branches widely in the tectum and makes a profusion of synapses, distributed over a large area of tectum that over- laps with the territories innervated by other axons. These territories are subse- quently trimmed back by selective elimination of synapses and retraction of axon branches. This is accompanied by the formation of new sprouts, through which each axon develops a denser distribution of synapses in the territory that it retains.
A central part in this remodeling and refinement of the map is played by two competition rules that jointly help to create spatial order: (1) axons from sepa- rate regions of retina, which tend to be excited at different times, compete to dominate the available tectal territory, but (2) axons from neighboring sites in
A P A P A P A P A P A P neurons from nasal half of retina
(B) P A P A P A P A P
(A) temporal nasal
neurons from temporal half of retina
Figure 22–106Selectivity of retinal axons growing over tectal membranes.
(A) A photograph of the experimental observation. (B) A diagram of what is happening. The culture substratum has been coated with alternating stripes of membrane prepared either from posterior tectum (P) or from anterior tectum (A). In the photograph, the anterior tectal stripes are made visible by staining them with a fluorescent marker in the vertical strips at the sides of the picture. Axons of neurons from the temporal half of the retina (growing in from the left) follow the stripes of anterior tectal membrane but avoid the posterior tectal membrane, while axons of neurons from the nasal half of the retina (growing in from the right) do the converse. Thus anterior tectum differs from posterior tectum and nasal retina from temporal retina, and the differences guide selective axon outgrowth. These experiments were performed with cells from the chick embryo. (From Y. von Boxberg, S. Deiss and U. Schwarz, Neuron 10:345–357, 1993. With permission from Elsevier.)
the retina, which tend to be excited at the same time, innervate neighboring ter- ritories in the tectum because they collaborate to retain and strengthen their synapses on shared tectal cells (Figure 22–107). The mechanism underlying both these rules depends on electrical activity and signaling at the synapses that are formed. If all action potentials are blocked by a toxin that binds to voltage- gated Na+channels, synapse remodeling is inhibited and the map remains fuzzy. The phenomenon of activity-dependent synapse elimination is encoun- tered in almost every part of the developing vertebrate nervous system. Synapses are first formed in abundance and distributed over a broad target field; then the system of connections is pruned back and remodeled by competitive processes that depend on electrical activity and synaptic signaling. The elimina- tion of synapses in this way is distinct from the elimination of surplus neurons by cell death, and it occurs after the period of normal neuronal death is over.
Much of what we know about the cellular mechanisms of synapse formation and elimination comes from experiments on the innervation of skeletal muscle in vertebrate embryos. A two-way exchange of signals between the nerve axon terminals and the muscle cells controls the initial formation of synapses. At sites of contact, acetylcholine receptors are clustered in the muscle cell membrane and the apparatus for secretion of this neurotransmitter becomes organized in the axon terminals (discussed in Chapter 11). Each muscle cell at first receives synapses from several neurons; but in the end, through a process that typically takes a couple of weeks, it is left innervated by only one. The synapse retraction again depends on synaptic communication: if synaptic transmission is blocked by a toxin that binds to the acetylcholine receptors in the muscle cell membrane, the muscle cell retains its multiple innervation beyond the normal time of elim- ination.
Experiments on the musculoskeletal system, as well as in the retinotectal system, suggest that it is not only the amount of electrical activity at a synapse that is important for its maintenance, but also its temporal coordination. Whether a synapse is strengthened or weakened seems to depend critically on whether or not activity in the presynaptic cell is synchronized with activity of the other presynaptic cells synapsing on the same target (and thus also synchro- nized with activity of the target cell itself ).
These and many other findings have suggested a simple interpretation of the competition rules for synapse elimination in the retinotectal system (Figure 22–108). Axons from different parts of the retina fire at different times and so com- pete. Each time one of them fires, the synapse(s) made by the other on a shared tectal target cell are weakened, until one of the axons is left in sole command of
retinal neurons retinal axons tectal neurons
FUZZY INITIAL MAP: DIFFUSE CONNECTIONS SHARP FINAL MAP: DIFFUSE CONNECTIONS ELIMINATED
Figure 22–107Sharpening of the retinotectal map by synapse elimination. At first the map is fuzzy
because each retinal axon branches widely to innervate a broad region of tectum overlapping the regions innervated by other retinal axons. The map is then refined by synapse elimination. Where axons from separate parts of the retina synapse on the same tectal cell, competition occurs,
eliminating the connections made by one of the axons. But axons from cells that are close neighbors in the retina cooperate, maintaining their synapses on shared tectal cells. Thus each retinal axon ends up innervating a small tectal territory, adjacent to and partly overlapping the territory innervated by axons from neighboring sites in the retina.
that cell. Axons from neighboring retinal cells, on the other hand, tend to fire in synchrony with one another: they therefore do not compete but instead main- tain synapses on shared tectal cells, creating a precisely ordered map in which neighboring cells of the retina project to neighboring sites in the tectum.