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 previously to a peripheral site of action of the nAChR-blocking agents at the neuromuscular junction (NMJ), because nAChRs are expressed in both muscle and spinal cord, it has been suggested that the rescue effect may, in fact, be mediated by a direct central action of nAChR antagonists. By using a variety of different nAChR-blocking agents that target specific muscle or neuronal nAChR subunits, we find that only those agents that act on muscle-type receptors block neuromuscular activity and rescue MNs. However, paralytic, muscular 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 MN survival. Taken together, the data presented here support the argument that, in vivo, nAChR antagonists promote the survival of spinal MNs primarily by acting peripherally at the NMJ to inhibit synaptic transmission and reduce or block muscle activity. Although a central action of these agents involving direct perturbations of MN activity may also play a contributory role, further studies are needed to determine more precisely the relative roles of central versus peripheral sites of action in MN rescue.
Oppenheim
R W
RW
Department of Neurobiology and Anatomy and the Neuroscience Program, Wake Forest University Medical School, Winston-Salem, North Carolina 27157-1010, USA. roppenhm@wfubmc.edu
Prevette
D
D
D'Costa
A
A
Wang
S
S
Houenou
L J
LJ
McIntosh
J M
JM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002038:Bungarotoxins / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002642:Chick Embryo; D003472:Curare / Q000494:pharmacology; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009068:Movement / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D009469:Neuromuscular Junction / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D010525:Peripheral Nerves / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure
D002038:Bungarotoxins; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D003472:Curare