The Anatomy of the Neuromuscular Junction Is Specialized for One-Way Synaptic Communication

Motor neurons that synapse on skeletal muscles have their cell bodies located within the central nervous system (CNS), either within the spinal cord or the brainstem. The axons of these motor neurons travel within peripheral nerves, out to the muscle, where each motor neuron synapses on several individual fibers (cells) of the muscle. However, an individual skeletal muscle fiber receives synaptic input from, and therefore its contraction is controlled by, only one motor neuron.

The neuromuscular junction, like most chemical synapses, has (1) a presynaptic side; (2) a narrow space between the neuron and muscle fiber, called the synaptic cleft; and (3) a postsynaptic side (see Figure 5-1). The presynaptic side of the synapse is made up of the terminal (transmitting) portion of the motor neuron. This presynaptic terminal has a swelled, buttonlike appearance and is also called a synaptic bouton. The terminal (or synaptic bouton) contains a large number of membranous storage vesicles, called synaptic vesicles, which contain the chemical neurotransmitter substance, in this case acetylcholine. These synaptic vesicles are lined up in rows along the inner surface of the terminal membrane (Figure 5-2). The presynaptic membrane region associated with each double row of vesicles is called an active zone and is the site where the synaptic vesicles will eventually release acetylcholine into the synaptic cleft. The presynaptic terminal also contains mitochondria, an indication of active metabolism in the cytoplasm. Some mitochondrial products (e.g., acetyl-CoA, ATP) play a role in the local synthesis of acetylcholine and in its movement into the synaptic vesicles.

The presynaptic (neural) and postsynaptic (muscle) cell membranes are separated by a narrow space, the synaptic cleft, that is about 50 nm wide (see Figures 5-1 and 5-2). The cleft contains extracellular fluid and a basal lamina, composed of a matrix of molecules, that is a specialized region of the muscle basement membrane. Some of these matrix molecules mediate synaptic adhesion between neuron and muscle.

The postsynaptic muscle cell membrane has several specialized features that facilitate synaptic transmission. Directly opposite the face of the presynaptic terminal, the postsynaptic muscle cell membrane contains receptors for the acetylcholine transmitter (see Figures 5-1 and 5-2). In this focal region the membrane has a series of invaginations, called junctional folds, that increase the surface area where acetylcholine receptors can reside. The acetylcholine receptors are most densely packed at the mouth of these junctional folds, and these mouths are closely aligned with the active zones of the presynaptic terminals from which the acetylcholine is released. Thus, there is a good match between the focal region of transmitter release from the neuron and the focal location of the receptors on the muscle fiber. Because the neurotransmitter is found only on the presynaptic neural side of the neuromuscular junction, transmission can go only from neuron to muscle, not in the reverse direction. Also, it should be noted that a motor neuron gives off several presynaptic terminals (synaptic boutons) to an individual muscle fiber. Together, this cluster of terminals is localized to a restricted region of the muscle fiber.

As noted, neurotransmitter signaling across the neuromuscular junction, for purposes of activating muscle fiber contraction, favors the nerve to muscle direction. However, there is some evidence that other types of molecules, in the muscle, may play a role during development in the survival, differentiation, and normal functioning of the presynaptic motor neuron terminals.

An Action Potential on the Presynaptic Neuron Triggers an Action Potential on the Muscle Cell Through the Release of Acetylcholine

The function of the neuromuscular junction is to transmit a chemical message unidirectionally between a motor neuron and a skeletal muscle cell (fiber) with a frequency established by the CNS. The arrival of an action potential at the motor neuron terminal triggers the release of the acetylcholine transmitter, which then binds with acetylcholine receptors on the postsynaptic muscle fiber membrane. This leads to the genesis of an action potential along the muscle fiber membrane that ultimately leads to contraction of the fiber.

An action potential on a motor neuron arises at its initial axon segment and then travels along the entire axon, eventually arriving at the presynaptic terminal (see Chapter 4). As previously noted, the exchange of Na⁺ and K⁺ ions, across axonal voltage-gated Na⁺ and K⁺ channels, is responsible for the generation of the action potential and its conduction to the terminal. However, as the action potential arrives at the presynaptic membrane, the wave of depolarization opens voltage-gated Ca²⁺ channels located in this region (see Figure 5-2); as Ca²⁺ flows toward equilibrium across the membrane, the Ca²⁺ enters the presynaptic terminal. This increase in the intracellular Ca²⁺ level is critical for the release of neurotransmitter from the terminal.

Recall that the acetylcholine-containing synaptic vesicles are lined up at the active zones of the presynaptic terminal. They will dock there by the intertwining of binding proteins that respectively reside on the vesicle membrane (synaptobrevin) and on the inner surface of the terminal membrane (syntaxin and SNAP-25) (Figure 5-3). This holds the vesicles near the location of Ca²⁺ entry given that the voltage-gated Ca²⁺ channels are efficiently located in the vicinity of these active zones. When Ca²⁺ flows into the terminal, the ion binds with yet another protein on the synaptic vesicle membrane (synaptotagmin). This triggers fusion of the vesicle with the presynaptic membrane, opening of the vesicle, and release of acetylcholine into the synaptic cleft. After transmitter release, the vesicle membrane is retrieved back into the presynaptic terminal and can be recycled to re-form a vesicle that is then refilled with acetylcholine synthesized in the cytoplasm. Certain bacterial toxins (e.g., botulinum, tetanus) can destroy the binding proteins involved in vesicle docking, ultimately interfering with the ability of the vesicle to release its contents into the synaptic cleft.