Synaptic Transmission (The Neuron) Part 2

Clinical Considerations

Diseases Affecting the Chemical Transmission at the Nerve-Muscle Synapse

Myasthenia Gravis

Myasthenia gravis means "severe muscle weakness." It is an autoimmune disease in which the number of functional nAChRs in the postsynaptic membrane at the motor end-plate is reduced.In this disorder, antibodies against the nAChRs (probably produced by T and B lymphocytes) are present in the serum of patients who have the disease. The antibodies bind with nAChRs at the motor end-plate and reduce the number of these receptors. Thus, muscular weakness is elicited due to a decrease in the response of the muscle fiber to Ach. The symptoms of myasthenia gravis include weakness of the eyelids, eye muscles, oropharyngeal muscles, and limb muscles. The muscle weakness is increased during exercise and reduced by rest. Standard therapy for patients with myasthenia gravis includes administration of anticholinesterase drugs (e.g., neostigmine). These drugs can reverse the muscle weakness. Inhibition of acetylcholinesterase allows the released Ach to remain unhydrolyzed for a longer time and increases the chances of its interaction with the nAChRs.

In some patients, removal of the thymus improves the symptoms. It should be recalled that T lymphocytes, which are responsible for cell-mediated immunity, develop in the thymus and B lymphocytes, which produce antibodies, develop in bone marrow. In myasthenia gravis, T cells become reactive against the nAChR. Infection with a virus containing an amino acid sequence similar to that in the nAChR may activate the T cells.

Lambert-Eaton (Eaton-Lambert) Syndrome

Defects in Myelination

Charcot-Marie-Tooth Disease

In Schwann cells of the myelin sheath, successive layers of myelin are connected with gap junctions, which allow flow of ions and small metabolites between these myelin layers. A form of Charcot-Marie-Tooth disease is characterized by demyelination, which is caused by a mutation in one of the connexin genes expressed in the Schwann cells. As a result of this mutation, connexin fails to form functional gap junction channels, which are essential for the normal flow of metabolites in the Schwann cells. One of the consequences of this defect is the impairment in the myelina-tion process. Demyelination may affect both motor and sensory nerves. Typically, there is weakness of the foot and lower leg muscles causing foot drop and a high-stepped gait with frequent tripping or falls. Foot deformities, such as high arches and hammertoes (a condition in which the middle joint of a toe bends upwards) due to weakness of the small muscles in the feet can occur. The lower legs may appear like an "inverted champagne bottle" due to the loss of muscle bulk. At advanced stages of the disease, weakness and muscle atrophy can occur in the hands, resulting in difficulty with fine motor skills. Damaged nerve fibers send incorrect signals to pain centers resulting in mild or severe neuropathic pain characterized by shooting and burning pain, tingling, and numbness. The patients may exhibit hyporeflexia. In rare cases, there is respiratory muscle weakness. The symptoms are usually experienced in adolescence, early adulthood, or middle adulthood. This disease is not considered to be fatal, and patients suffering from it can have a normal life expectancy. There is no cure for this disease. Patients are usually advised to undergo physical therapy and occupational therapy. Some patients might need to rely on foot or leg braces or other orthopedic devices to maintain mobility. Orthopedic surgery may enable some patients to cope with the symptoms of the disease. Analgesics are prescribed for some patients who have severe pain.

Disorders Associated With Toxins

It is necessary to know the following acronyms in order to understand the mechanism of action of botulinum and tetanus toxins: "SNARE" stands for "SNAP Receptors," "SNAP" stands for "Soluble NSF Attachment Protein," and "NSF" stands for "N-ethylmaleimide Sensitive Fusion Protein." SNARE proteins include synaptobrevin (present in vesicular membrane), syntaxin (present in presynaptic membrane, and SNAP-25 (present in presynpatic membrane). Synaptotagmin is a calcium-binding protein present in vesicular membrane.

Botulism

Botulinum toxin is produced by anaerobic clostridium bacteria. Botulism can occur when food contaminated by this toxin is consumed. Botulinum toxin abolishes neuro-transmitter release at the neuromuscular junction, which results in paralysis of the diaphragm causing respiratory failure and skeletal muscle weakness. Visceral motor dysfunction can occur due to the blockade of synapses in smooth muscles. Botulinum toxin preferentially affects motor neurons. Botulinum toxin is a specific protease that cleaves SNARE proteins present in the vesicular and pre-synaptic cell membranes. These SNARE proteins are involved in exocytosis.Interruption of exocytosis prevents the release of excitatory neurotrans-mitter at the neuromuscular junction. The patients suffering from botulism need intensive medical and nursing care. Because of respiratory failure, the patient requires artificial ventilation for weeks. If diagnosis is made early, botulism can be treated by inducing passive immunity with a horse-derived antitoxin. The antitoxin blocks the action of the circulating toxin. Some antibiotics (e.g., aminoglycosides or clindamycin) may worsen paralysis in botulism because these bacteria release toxin.

Tetanus

Tetanus is caused by infection of open wounds by clostrid-ium bacteria that produce tetanus toxin. This toxin is preferentially taken up by inhibitory spinal interneurons. Damage to inhibitory spinal interneurons results in disin-hibition of spinal motor neurons. Consequently, there is hyperexcitation of skeletal muscles, which results in tetanic contractions. Tetanus toxin is a protease that cleaves SNARE proteins involved in exocytosis, resulting in the abolition of inhibitory neurotransmitter in spinal interneurons. Treatment consists of controlling muscle spasms, stopping toxin production, and neutralizing the effects of the toxin. Tetanus immune globulin consisting of antibodies that bind to the tetanus toxin (tetanus antitoxins) are administered. Large doses of antibiotics (e.g., met-ronidazole or intramuscular penicillin G) are administered to reduce toxin production. Tetanus is a vaccine-preventable disease. Administration of tetanus toxoid vaccine provides protection from tetanus for about 10 years.

Clinical Case

History

Sonia is a 49-year-old woman with a history of heavy smoking for many years. For the past couple of months, she noticed a generalized progressive weakness in her neck, arms, and leg muscles. She also suffered from constipation, and her mouth remained dry. When she stood up or walked, she often experienced a short period of dizziness. She consulted her internist, who gave her a battery of tests in the local hospital. She was then admitted to the hospital for further examination and treatment.

Examination

An initial evaluation resulted in a diagnosis of lung cancer, as a result of having smoked for many years.This diagnosis was confirmed bya histological examination revealing the presence of a small-cell carcinoma of the lung. The physical examination also showed weakness of the neck flexors, arms, and legs. Electromyograms (EMGs) and nerve conduction tests were given. These tests involved electrical stimulation of the ulnar nerve, by placing an electrode on her wrist, and recording of compound motor action potentials in the muscles controlling her little finger.The amplitude of the compound motor action potential in this muscle was reduced. She was asked to exercise her hand muscles vigorously, and nerve conduction and EMG tests were repeated. Following the exercise, a marked improvement was observed in the amplitude of the compound motor action potential in the muscle being recorded.in addition,Sonia’s muscle function improved briefly after the intravenous administration of edrophonium (Tensilon).

Explanation

This is an example of an autoimmune disorder, called the Lambert-Eaton (Eaton-Lambert) syndrome.The disorder occurs commonly in patients who have lung or breast cancer. Antibodies to Ca2+ (calcium) channels have been demonstrated to be present in these patients. A reduction of presynaptic Ca2+ channels results in reduced release of acetylcholine (Ach) from these terminals at the neuromuscular junction. It should be noted that in another autoimmune disorder, myasthenia gravis, antibodies to nAChRs are present, which also cause muscle weakness. In both the Lambert-Eaton syndrome and myasthenia gravis, administration of a short-acting acetylcholinesterase inhibitor (edrophonium [Tensilon]) improves muscle function.The enzyme, acetylcholinesterase, present at the neuromuscular junction, normally hydrolyzes Ach released from the nerve terminals innervating the skeletal muscle.Inhibition of this enzyme by edrophonium increases the availability of Ach at the neuromuscular junction, causing an improvement in the muscle function. The two disorders can be distinguished by EMG and nerve conduction tests. Repetitive nerve stimulation or vigorous muscle exercise improves muscle function in patients with the Lambert-Eaton syndrome, whereas muscle function deteriorates following vigorous exercise in patients with myasthenia gravis. Sonia was administered the corticosteroid prednisone intravenously for several days, which was then followed by further administration of this drug orally.Other approaches used to treat patients suffering from Lambert-Eaton syndrome include direct treatment of the tumor by standard radiation and chemotherapy and attempts at suppression of the immune system.

SUMMARY TABLE

Comparison of Transmission at the Peripheral Synapse (Neuromuscular Junction) and a Central Synapse

CNS = central nervous system

Diseases Associated With Synaptic Transmission

Ach = acetylcholine; nAchRs = nicotinic acetylcholine receptors; NMJ = neuromuscular junction; Ca²⁺ = calcium.