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Neuromuscular Junction NMJ And Synapses

Neuromuscular Junction (NMJ) And Synapses
In 1897 Sherrington coined the term synapse to mean the junction of two neurones. Much of the early work on the synapse was carried out on the cholinergic neuromuscular junction (NMJ), although it appears that this chemical synapse is similar in its mode of action to those found in the central nervous system (CNS). The chemical synapse is the predominant synapse type found in the nervous system, but electrical synapses are found in certain sites, e.g. glial cells (see Chapter 13).

Neuromuscular transmission (a model for synaptic transmission)
The sequence of events at a chemical synapse is as follows:
1.    The arrival of the action potential leads to the depolarization of the presynaptic terminal (labelled (1) on figure) with the opening of voltage-dependent Ca2+ channels in the active zones of the presynaptic terminal and subsequent Ca2+ influx (2) (this is the stage that represents the major delay in synaptic transmission).
2.    The influx of Ca2+ leads to the phosphorylation and alteration of a number of presynaptic calcium-binding proteins (some of which are found in the vesicle membrane) which liberates the vesicle from its presynaptic actin network allowing it to bind to the presynaptic membrane (3). These proteins include various different soluble NSF attachment proteins (SNAPs) and SNAP receptors (SNAREs).
3.     The fusion of the two hemichannels (presynaptic vesicle and presynaptic membrane) leads to the formation of a small pore that rapidly expands with the release of vesicular contents into the synaptic cleft. The vesicle membrane can then be recycled by endocytosis into the presynaptic terminal, either by a non-selective or more selective clathrin and dynamin-mediated process. More recently an alternative form of vesicle release has been described called ‘kiss and run’ exocytosis or flicker-fusion and this describes the formation of a transient fusion pore between the vesicle and the presynaptic membrane.
4.      Most of the released neurotransmitter then diffuses across the synaptic cleft and binds to the postsynaptic receptor (4). Some transmitter molecules diffuse out of the synaptic cleft and are lost, while others are inactivated before they have time to bind to the postsynaptic membrane receptor. This inactivation is essential for the synapse to function normally and, although enzymatic degradation of acetylcholine (ACh) is employed at the NMJ, other synapses use uptake mechanisms with the recycling of the transmitter into the presynaptic neurone (see Chapter 18).
5.      The activation of the postsynaptic receptor leads to a change in the postsynaptic membrane potential. Each vesicle contains a certain amount or quantum of neurotransmitter, whose release generates a small postsynaptic potential change of a fixed size – the miniature end plate potential (mepp). The release of transmitter from several vesicles leads to mepp summation and the generation of a larger depolarization or end-plate potential (epp) which, if sufficiently large, will reach threshold for action potential generation in the postsynaptic muscle fibre (5).
This vesicle hypothesis has been criticized, because not all CNS synapses contain neurotransmitters in vesicles and because electrical synapses are found in some neural networks. However, it is clear that electrical and chemical synapses can coexist in the same neurones and also it is increasingly recognized that neurones may communicate with each other through a range of non-synaptic mechanisms.

Neuromuscular Junction (NMJ) And Synapses

Disorders of neuromuscular transmission
A number of naturally occurring toxins can affect the NMJ.
   Curare binds to the acetylcholine receptor (AChR) and prevents ACh from acting on it and so induces paralysis. This is exploited clinically in the use of curare derivatives for muscle paralysis in certain forms of surgery.
   Botulinum toxin prevents the release of ACh presynaptically. In this case an exotoxin from the bacterium Clostridium botulinum binds to the presynaptic membrane of the ACh synapse and prevents the quantal release of ACh. The accidental ingestion of this toxin in cases of food poisoning produces paralysis and autonomic failure (see Chapter 3). However, the toxin can be used therapeutically in small quantities by injecting it into muscles that are abnormally overactive in certain forms of focal dystonia – a condition in which a part of the body is held in a fixed abnormal posture by overactive muscular activity (see Chapter 42). It is also used in cosmetic surgery to get rid of wrinkles.
A number of neurological conditions affect the NMJ selectively. These include myasthenia gravis, Lambert–Eaton myasthenic syn- drome (LEMS) and neuromyotonia or Isaac’s syndrome.
 In neuromyotonia the patient complains of muscle cramps and stiffness as a result of continuous motor activity in the muscle. This is often caused by an antibody directed against the presynaptic voltage gated K+ channel, so the nerve terminal is always in a state of depolarization with transmitter release.
  In LEMS there is an antibody directed against the presynaptic Ca2+ channel, so that on repeated activation of the synapse there is a steady increase in Ca2+ influx as the blocking antibody is competitively overcome by exogenous Ca2+. The patient complains of weakness, especially of the proximal muscles, which transiently improves on exercise.
  Myasthenia gravis, on the other hand, is caused by an antibody against the AChR, and patients complain of weakness that increases with exercise (fatigability) involving the eyes, throat and limbs. This weakness is due to the number of AChRs being reduced and the ACh released presynaptically competes for the few available receptors. More recently, a second antibody has been recognized in myasthenia gravis in patients without antibodies to the AChR. This antibody is directed to a muscle specific kinase (MUSK), although exactly how this causes the syndrome is not fully known.

Electrical synapses
Electrical transmission occurs at a small number of sites in the brain. The presence of fast conducting gap junctions promotes the rapid and widespread propagation of electrical activity and thus may be important in synchronizing some aspects of cortical function (see Chapter 43). However unlike chemical synapses, electrical synapses:
   are not unidirectional in terms of transmission of electrical information;
   do not contain a synaptic cleft;
   do not allow for synaptic integration.
The abnormal absence of gap junctions in Schwann cells leads to one form of peripheral hereditary motor sensory neuropathy.