There are a number of reasons, both historical and practical, for the popularity of the vertebrate neuromuscular junction (NMJ) in studies of synaptogenesis. Many of the seminal studies on the quantal nature of synaptic transmission were performed at the NMJ, establishing a battery of techniques for analysis and allowing a correlation of synaptic structure and function. The NMJ is also very accessible, with motor neuron input contacting each muscle approximately in the middle, and each muscle fiber receiving input from a single motor axon under normal circumstances in the adult. Thus, reliably finding a well-defined NMJ for

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experiments is trivial compared to repeatedly finding a well-defined population of central nervous system (CNS) synapses. The NMJ is also very large, and each nerve terminal is composed of many active zones (Figure 1.1), which is a benefit to physiological, ultrastructural, and imaging studies. Finally, and importantly, related synapses were amenable to biochemical analyses. Specifically, the electric organs of rays such as Torpedo californica are essentially huge stacks of cholinergic synapses that functionally and molecularly most closely resemble NMJs. Several key proteins found at cholinergic NMJs, including agrin, rapsyn, and even acetylcholine receptors (AChRs) themselves, were first characterized in such preparations.

Figure 1.1. The Neuromuscular Junction. The NMJ is the synapse between motor neurons and their target muscle fibers. In vertebrates, the motor neuron has a terminal ending with multiple presynaptic release sites. Synaptic vesicles containing the neurotransmitter acetylcholine, as well as ATP, are polarized in the terminal and cluster near thickenings in the presynaptic membrane, the active zones. The nerve terminal is recessed into the muscle cell membrane, and the entire structure is capped by a nonmyelinating glial cell, the terminal Schwann cell. The muscle fiber has invaginations, junctional folds, which are in direct apposition to the presynaptic active zones. An extracellular matrix runs through the entire synaptic cleft. At individual release sites, vesicles fuse with the presynaptic membrane and release neurotransmitter into the cleft. The acetylcholine receptors in the postsynaptic membrane are at their highest concentration near the crests of the junctional folds. The extracellular matrix contains many signaling and structural molecules, as well as acetylcholinesterase, the enzyme that degrades ACh and thus curtails synaptic transmission.

As a synapse, the NMJ is quite specialized. Most CNS neurons function as integrators, balancing excitatory and inhibitory synaptic inputs, and rarely firing an action potential in response to a single stimulus. The NMJ, however, functions as a failsafe synapse, where an action potential in the motor neuron is guaranteed to produce sufficient depolarization in the muscle fiber to reach the threshold for a muscle action potential, leading to contraction. To ensure this is the case, there is an extreme accumulation of AChRs, which function as ligand-gated cationic channels, and voltage-gated sodium channels in the postsynaptic membrane (Figure 1.1). In addition, the multiple release sites of the presynaptic terminal have a

Synaptic Plasticity

high cumulative probability of vesicular release in response to an action potential, and the amount of acetylcholine (ACh) released locally saturates postsynaptic receptors. Transmission is limited spatially and temporally by acetylcholinesterase (AChE) in the synaptic cleft, which degrades the transmitter, terminating the signal.

There are structural correlates to the functional requirements described above (Figure 1.1). Each of the many presynaptic active zones, the sites of vesicular release, is directly aligned with a postsynaptic specialization called a junctional fold. The folds are invaginations into the muscle plasma membrane. The highest concentration of AChRs is found near the tops of these folds, while the voltage-gated sodium channels are found deeper in the folds. This intimate arrangement of channels and increased membrane surface area provided by the folds helps ensure large synaptic currents and threshold depolarization. Another important structural feature of the NMJ is the thick basal lamina of extracellular matrix (ECM) that runs through the cleft. As mentioned above, this matrix contains AChE, which is important for synaptic function. In addition, it houses many of the signaling and structural molecules that are now known to be essential players in the development and stability of the NMJ.

From the studies of NMJ formation, a number of principles have become clear. First, there is a great deal of specialization and organization of both the pre-and postsynaptic components. This level of organization is not an absolute prerequisite for synaptic transmission, but is required for optimized synaptic function. Second, there is reciprocal signaling between the pre- and postsynaptic cells to achieve this functional optimization. This reciprocal signaling occurs during the formation and maturation of the NMJ, and also in adulthood, in cases of plasticity due to changes in synaptic efficacy or motor neuron loss. Third, components of the ECM serve critical signaling and structural roles during the formation and maturation of the synapse. Of these principles, the first two clearly apply to CNS synapses also. The role of the ECM may be somewhat specific for the NMJ, but analogous secreted signaling factors and transmembrane adhesion molecules serve these purposes in the brain (see Chapter 11).

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