Chapter 2 Reliability of neuromuscular transmission and how it is maintained

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An important function of all nervous systems is to control muscle contraction so that movements of the body are appropriate to promote survival. In most species, specialized motor neurons convey the signals that represent the neural commands for contraction from the central nervous system to the muscle fibers. This chapter describes the process of neuromuscular transmission. The chapter emphasizes on how the properties of the neuro muscular junctions (NMJs) ensure the reliability of transmission in a wide range of biological circumstances and how changes to those properties may lead to impaired transmission in disease. The main features of neuromuscular transmission, in addition to the essential presynaptic and postsynaptic aspects of neuromuscular transmission, are also described in the chapter. The chapter describes the measurement of safety factors and some of the modulating influences on the safety factor during normal use. The chapter accounts for several important aspects of the “biology” and adaptive plasticity of the NMJ, triggered by trauma or intoxication that promotes maintenance of the effective neural control of muscle. The principles of the functional organization of the NMJ can inform efforts to understand impaired neuromuscular transmission in disease. This account of neuromuscular transmission and its reliability is based on studies of a small number of laboratory species. The emphasis is on mammals, including humans. While neuromuscular transmission in different species has much in common, there are also many important differences. It is therefore always necessary to use caution when trying to interpret findings in one species on the basis of knowledge of another. The ability of the NMJ to recover from a wide variety of mechanical and chemical assaults indicates the evolutionary importance of effective and reliable neuromuscular transmission.

Section snippets

An introduction to neuromuscular transmission

An important function of all nervous systems is to control muscle contraction so that movements of the body are appropriate to promote survival. In most species specialized motor neurons convey the signals that represent the neural commands for contraction from the central nervous system to the muscle fibers. These signals are transmitted to the individual muscle fibers at highly differentiated neuromuscular junctions (NMJs). In vertebrates, the process of neuromuscular transmission involves

Introduction to the quantal release of ACh

ACh quanta are released from the motor nerve terminal within 100 μs or so of the arrival of the nerve impulse (Katz 1969, Van der Kloot 1994). The events that allow the conversion of depolarization into secretion are complex. At the normal mammalian NMJ, they result in the release of more than enough ACh to ensure a postsynaptic depolarization that evokes an action potential in the muscle fiber (Wood and Slater, 2001). This section presents an account of the main events in the release process.

Diffusion of ACh in the cleft

The rising phase of the EPC lasts about 0.2 ms. During this time, ACh released from the nerve must diffuse across the synaptic cleft, bind to AChRs, which must then undergo a conformational change (“opening”), and Na+ ions must diffuse into the muscle fiber to generate the EPC. The ACh released from a single vesicle diffuses rapidly in the synaptic cleft, with an estimated diffusion coefficient of 1.4 × 10−6 cm2s−1 (Krnjević and Mitchell, 1960). In 0.2 ms, the mean diffusion distance of an ACh

Safety factor of neuromuscular transmission: definition and measurement

The previous sections have described the two core aspects of neuromuscular transmission: the quantal release of ACh by the nerve impulse and the action of that ACh on the muscle fiber to initiate an action potential. In practice, it is the balance between these two processes that determines whether the neural activation of muscle is successful. Many studies have shown that in a wide variety of conditions more ACh is released by each nerve impulse than is required to excite the muscle fiber. The

Modulation of safety factor during normal use

Why is the safety factor for neuromuscular transmission so high? During natural use of the neuromuscular system, the pattern and amount of activity change over a wide range. The ability of the nerve to release transmitter varies significantly as the frequency of activation changes. In particular, during high frequency activity, the quantal content declines significantly. Most published estimates of quantal content that have been used to estimate safety factor (Table 2.1) were determined at low

Biological aspects of safety factor

The description presented so far of the factors that determine the reliability of neuromuscular transmission has been concerned almost entirely with the mature NMJs of normal adult animals. Further, although some mention has been made of differences between the NMJs of frogs and mammals, little attention has been paid to how NMJs in different species, or even within the same species, might differ. The first part of Section 2.6 will consider how NMJs vary between and within species. While a

Response of the neuromuscular junction to trauma or intoxication

The vertebrate neuromuscular system, including the NMJ, is extremely good at repairing itself and restoring function after many sorts of damage. Several different types of cellular mechanism contribute to this ability and help to ensure that effective and reliable activation of muscle is maintained or re‐established. Thus motor axons regenerate well and can form new presynaptic terminals in a few days. For their part, muscle fibers can regenerate after complete destruction and accept and

Overview

The efficacy and reliability of neuromuscular transmission depend on many factors operating at numerous levels of functional organization. As a result many molecules could be targets of pathogenic processes that might interfere with the reliability of neuromuscular transmission. It is perhaps surprising, therefore, that diseases in the NMJ are rare. For example, myasthenia gravis (MG), the most common disease affecting the NMJ directly, has a prevalence in Western countries of only 10–20/100

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