Multiple events triggered by the use of botulinum neurotoxins at the vertebrate neuromuscular junction

The three main cellular components of the neuromuscular junction (NMJ) are affected by a single local injection of botulinum neurotoxin (BoNT). Motor nerve terminals are known to synthesize and release acetylcholine (ACh) spontaneously, or in response to nerve stimuli. The main action of BoNTs is to reduce the number of ACh quanta released, without affecting transmitter synthesis and storage. According to the serotype used, quantal ACh release remains synchronized (BoNT/A, /E, and /C), or is desynchronized (BoNT/B, /D, /F/ and /G). These effects are related to the synaptic proteins cleaved by BoNTs. The reduction in quantal ACh release prevents nerve-evoked synaptic responses to reach the threshold for action potential generation in muscle fibres and blocks nerve- evoked muscle contractions. The duration of the neuromuscular block depends on the BoNT serotype, the dose injected, and the animal species considered. Muscle inactivity in turn induces an important atrophy of muscle fibres, with no evident damage to NMJ components, and triggers an overgrowth of intramuscular axons, nerve terminals, and perisynaptic Schwann cells. The events leading to the maturation of the newly formed sprouts, the development of the first nerve–muscle contacts, the differentiation of new endplates, and the elimination of superfluous synapses after BoNTs injection is a remarkable demonstration of synaptic plasticity at the mature NMJ.