Organophosphate intoxication in C. elegans reveals a new route to mitigate poisoning through the modulation of determinants responsible for nicotinic acetylcholine receptor function

Plasticity is a reactive mechanism that allows the adaptation of organisms to changing environmental cues. The exploitation of this physiological process has a clear benefit to promote the recovery from a wide range of neurological disorders. Here, we show that plasticity-promoting regimes provide candidate mechanisms to supplement the classically used antidotes for anti-cholinesterase poisoning. These neurotoxins inhibit acetylcholinesterase, causing the overstimulation of cholinergic transmission at synapses and neuromuscular junctions. The model organism C. elegans exhibits organophosphate-induced mitigating plasticity that impacts on the recovery of neuromuscular phenotypes, initially impaired by the drug. This is underpinned by overstimulation of nicotinic receptors at the neuromuscular junction. Intrinsic determinants of receptors location and sensitivity modulate the extent of plasticity in the context of persistent cholinergic stimulation. Our results indicate that pharmacological intervention of nicotinic receptors and/or scaffolding proteins that support receptor function might provide a novel treatment route for anti-cholinesterase poisoning.