Effect of β2-adrenergic receptor agonists on neurotransmission and neuromuscular junction structure in congenital myasthenic syndromes

Thesis

Background: β2-adrenergic agonists have been reported to be beneficial in patients with congenital myasthenic syndromes, in particular in those subtypes where postsynaptic structure is impaired. Although the β2-adrenergic receptor is well known for its muscle actions, its working mechanism at the neuromuscular junction is not understood.

Aims: It was hypothesized that β2-adrenergic agonists improve neurotransmission by ameliorating postsynaptic structure in congenital myasthenic syndromes.

Methods : The effect of β2-adrenergic agonists was studied on neuromuscular function and structure in mouse models of acetylcholine receptor (AChR) deficiency and DOK7 myasthenic syndrome, using electrophysiological and morphological techniques.

Results: β2-adrenergic agonists reduced muscle fatigability in the mouse model of AChR deficiency, and they temporarily halted failure to grow in the DOK7 myasthenic mouse model. β2-adrenergic agonists enhanced neurotransmission by counteracting the detrimental effect on postsynaptic neuromuscular junction structure either caused by the use of acetylcholinesterase inhibitors or by the DOK7 mutation. They promoted the formation of postsynaptic junctional folds.

Conclusion: β2-adrenergic agonists have a direct effect at the neuromuscular junction, via stabilising postsynaptic structure.

Authors: Vanhaesebrouck, A

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford