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Neuronal Survival/Synapse Elimination

At the neuromuscular junction, synapses compete for innervation of a muscle fiber. Although this competetion results in a reduction in the number of synaptic inputs to a muscle, the complexity of each synaptic input increases and the strength of each synapse increases.

Some Synapses Are Eliminated During Development

Synapse elimination at the neuromuscular junction involves a loss of AChRs and a withdrawal of the presynaptic terminal. Activity-dependent competition between motor axons favors more active inputs. Direct competition between nerve fibers favors the axon that is able to compete for trophic factors supplied by the target cell. Indirect competition allows the muscle to select the favored axon. An additional strategy for synapse elimination may be that the elimination is provoked by a retrograde messenger. Additional information about retrograde signaling are found in Chapter 14, part 3.

Figure 9.24

In the adult, almost all muscle fibers are innervated by a single motor neuron. However, early in development many postsynaptic targets are innervated by multiple nerve terminals (this is true for skeletal muscles). During synapse maturation many nerve terminals disappear. Synapse elimination is thought to occur by the withdrawal of presynaptic terminals. Although the number of distinct synaptic inputs to a given target decreases during this process, the complexity of individual remaining terminals actually increases (individual synapses become larger and have more complex structures). The net result of this process is an increase in the overall strength of individual synapses. This process of synapse elimination and rearrangement plays an important role in sculpting the circuitry of the nervous system and the fine tuning of individual synaptic contacts.

The development of connectivity in the central nervous system requires the initiation of synaptic contacts and the maintenance of the correct number of synapses. It is not clear why, but it seems that more synapses are created than are eventually required for proper neuronal function. Under these circumstances, some synapses are eliminated. The process of synapse elimination allows for a "use dependent" form of Darwinism; those synapses that are necessary are retained while those that are simply redundant are removed. The neuromuscular junction and the visual system have been used as models to provide insights into the molecular mechanisms underlying synapse elimination.

Synapse elimination can result from activity-dependent signals in the postsynaptic cell.
Figure 9.25 Postsynaptic receptor activation by active neronal inputs results in a stabilization of multiple inputs. Thus, when all of the receptors are activated simultaneously and their signalling processes (cloud) engaged, there is no loss of receptors (gray) from the synapse.	Figure 9.26 When two inputs are differentially activated, the active receptors are protected and the inactive ones are not, resulting in a loss of the inactive receptors and their associated presynaptic elements.	Figure 9.27 When all receptors are silent there is an even input to each synapse resulting in no synapse loss.

Summary

1. A neuron's ability to reach its target is essential for its survival.
2. During development, there is association between the number of presynaptic neurons and the size of their targets.
3. Synapse formation is a complex and gradual process.
4. Specific molecules from neurons and muscles play important roles in synapse formation and in regeneration (e.g., agrin).
5. Finally, synapse elimination and rearrangement result in the fine tuning of neuronal circuitry and synapse strengthening in the nervous system.
   

Cell Death, Injury/Regeneration, and Trophic Factors

In most developing tissues, substantial cell death occurs during development. One type of cell death occurs in an activity-dependent manner and is related to synapse elimination (see above). Cell death has been suggested to be the default pathway for all cells, and cells that escape do so by receiving appropriate trophic support. With the growing realization that pathological cell death shares features in common with cell death that occurs during development, a better understanding of developmental cell death may reveal potential therapeutic strategies for the treatment of neurodegenerative disorders and trauma.

The formation of synaptic connections between a presynaptic neuron and its target is often critical to the survival of the presynaptic neuron. In many cases if a synapse is not formed, or if an incorrect synapse is made, then the presynaptic neuron will eventually die. The survival of neurons is often dependent on trophic factors that are produced by the target tissue. Trophic factors are essential for neuron survival; their function is to promote cell growth. (Note: trophic factors should not be confused with chemotropic factors that attract cells.)