Reduction of neuromuscular activity is required for the rescue of motoneurons from naturally occurring cell death by nicotinic-blocking agents

Spinal motoneurons (MNs) in the chick embryo undergo programmed cell death coincident with the establishment of nerve-muscle connections and the onset of synaptic transmission at the neuromuscular junction. Chronic treatment of embryos during this period with nicotinic acetylcholine receptor (nAChR) blocking agents [e.g., curare or alpha-bungarotoxin (alpha-BTX)] prevents the death of MNs. Although this rescue effect has been attributed previousl y to a peripheral site of action of the nAChR-blocking agents at the neurom uscular junction (NMJ), because nAChRs are expressed in both muscle and spi nal cord, it has been suggested that the rescue effect may, in fact, be med iated by a direct central action of nAChR antagonists. By using a variety o f different nAChR-blocking agents that target specific muscle or neuronal n AChR subunits, we find that only those agents that act on muscle-type recep tors block neuromuscular activity and rescue MNs. However, paralytic, muscu lar dysgenic mutant chick embryos also exhibit significant increases in MN survival that can be further enhanced by treatment with curare or alpha-BTX , suggesting that muscle paralysis may not be the sole factor involved in M N survival. Taken together, the data presented here support the argument th at, in vivo, nAChR antagonists promote the survival of spinal MNs primarily by acting peripherally at the NMJ to inhibit synaptic transmission and red uce or block muscle activity. Although a central action of these agents inv olving direct perturbations of MN activity may also play a contributory rol e, further studies are needed to determine more precisely the relative role s of central versus peripheral sites of action in MN rescue.