Burges, Judith Clare; (1990) Impaired neuromuscular transmission: electrophysiological investigations in mouse and human muscles. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In this thesis, some aspects of impaired neuromuscular transmission have been investigated by electrophysiological means. Myasthenia gravis (MG) is an autoimmune muscle weakness disorder, caused by antibodies (Abs) directed against the acetylcholine receptor (AChR). However, in 10-15% of patients who show clinical symptoms of MG, there is no detectable anti-AChR antibody as shown by routine radioimmunoassays ("antibody-negative" patients). It is possible, however, that Abs may be present against sites other than the AChR in the latter patients. To investigate this, mice were injected with plasma (or the immunoglobulin G (IgG) fraction) from 7 patients, and intracellular recordings made from the mouse diaphragm muscles. Each plasma/IgG studied produced a significant reduction in miniature end-plate potential (mepp) amplitude. This did not appear to arise by a postsynaptic action since a-bungarotoxin binding and/or ACh sensitivity were unaffected. Also, analysis of voltage noise during ACh exposure showed no effect on single channel properties for those plasmas investigated. Furthermore, of the 7 plasmas studied, 4 gave significant reductions in end-plate potential (epp) quantal content. The results suggest an autoimmune basis of "antibody-negative" MG, with antibodies apparantly acting presynaptically, perhaps by interfering with vesicle packaging. Experiments were also performed to investigate the actions of anti-AChR Abs present in 85-90% of patients with MG. The effects of acute applications of the Ig fraction on biopsied human muscle were studied. Mepp amplitude was significantly reduced as compared to controls by the MG Ig. Thus acute blocking actions of anti-AChR Abs may be important in the pathogenesis of normal MG. Finally, possible modulation of neuromuscular transmission by the Ca2+ channel agonist CGP 28392 (2pM) was studied. This compound had no significant effect on epp quantal content, on mepp frequency in high potassium (K+) solutions or on mepp amplitude. Thus this agent had neither pre nor postsynaptic actions at this concentration. More specifically, since CGP 28392 is an agonist at L-type Ca2+ channels, L-type Ca2+ channels appear to play no major role in acetylcholine (ACh) release at the neuromuscular junction.

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