Background Therapies acting on the sympathetic nervous system have been shown to have beneficial effects in several neurological diseases. More recently, sympathomimetics have been shown to be beneficial in the management of congenital myasthenic syndromes (CMS). However, the mechanism by which the sympathetic nervous system exerts an effect on neuromuscular transmission is completely unknown. Current treatment strategies for CMS are limited in that they are poorly understood, of varying efficacy and often limited by side effects.

Aims The aim of the proposed research is to explore the mode of action of sympathomimetics on NMJ development and structure, and to characterise the principle route by which adrenergic modulation exerts a physiological effect.

Methods Our preliminary results show the adrenergic agonist salbutamol alleviates some of the pathology observed in zebrafish CMS models, resulting in improved motility and improved NMJ morphology. The effect of salbutamol and ephedrine will also be studied in CMS mouse models. Results from in vivo analysis will be contrasted with the effect of these sympathomimetics in vitro using nerve muscle co-cultures, allowing separate analysis of pre and postsynaptic effects of these drugs throughout NMJ maturation. We will characterise the effects on neurotransmission using functional, electrophysiological, immunohistological and proteomic analysis.