Synapse Formation: Competing Philosophies

Matthew S. Kayser

How does the nervous system form synapses during development? Much of what we know comes from the model system of the vertebrate neuromuscular junction (NMJ). The neuromuscular synapse is a reliable relay, so that an action potential traveling in a motor axon will consistently result in contraction of the muscle fiber it innervates. Interestingly, during development, multiple motor axons can innervate a muscle fiber initially (see figure), but at a mature NMJ just one axon innervates one muscle fiber. How is it decided which motor axon will innervate a given muscle fiber? The outcome is more analogous to Darwinian natural selection than Calvinist predestination: Motor axons engage in a competition for space on a muscle fiber.

Single mature neurons in the central nervous system (CNS)—in sharp contrast to single mature muscle fibers at the NMJ—receive thousands of inputs. That is, the dendrites of a single neuron may make synaptic contact with axons of thousands of other neurons. This raises the question of how the brain can possibly become wired properly. A leading hypothesis suggests molecular matchmaking occurs, wherein the appropriate axons and dendrites recognize cues on one another. Box Extension 13.1 describes more about how synapses form during development in the brain and at neuromuscular junctions.

At the NMJ, the process of motor axons competing for muscle fiber territory depends on firing activity in the axons. At a doubly innervated muscle fiber, inhibition of neurotransmission at one of the two axonal inputs results in the more active input taking over territory of the less active one. This competitive process occurs naturally over time:

Figure A Axonal input competition at developing neuromuscular junctions was observed in young mice (1) Multiple axons can innervate each muscle fiber at immature NMJs. In this image (on day 8 of postnatal development) some neurons have been labeled blue and others green. The postsynaptic receptors are red. The muscle fibers themselves are not visible. (2) A single immature NMJ monitored from day 11 to day 15 of postnatal development. The weaker input (in this case blue) gradually loses out to the stronger input (green), leaving only a single axon innervating the muscle fiber. (After Walsh and Lichtman 2003; courtesy of Jeff Lichtman.)

As shown in Part 2 of the figure, one axon at a multiply innervated muscle fiber is eliminated (blue in this example) while the other (green) takes over the entire NMJ. Thus we see that relatively more powerful inputs are favored in the competitive process of neuromuscular synapse maturation and elimination.

How does synapse formation in the CNS compare? Unlike a target muscle fiber, mature neurons in the CNS have thousands of synapses on average, making it hard to imagine that similar mechanisms could be at play. During NMJ formation, the same set of molecular cues guides synapse development at all junctions. In the CNS, in contrast, it appears possible that thousands of different molecular variants direct aspects of synapse formation. One attractive idea is that presynaptic axons and postsynaptic dendrites bear transmembrane cues, each capable of interacting only with its correct binding partner. In this manner, molecular matchmaking could occur, directing axons from a particular neuron to form stable synapses only on the proper target. Whereas this hypothesis implies that certain neurons are fated to find one another, a more likely scenario might be that molecular cues restrict axons to a small subset of neuronal targets, and that patterned activity based on external stimuli refines connectivity as development proceeds.

References

Walsh, M. K., and J. W. Lichtman. 2003. In vivo time-lapse imaging of synaptic takeover associated with naturally occurring synapse elimination. Neuron 37: 67–73.