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The Journal of Neuroscience, August 15, 2000, 20(16):6117-6124
Reduction of Neuromuscular Activity Is Required for the
Rescue of Motoneurons from Naturally Occurring Cell Death by
Nicotinic-Blocking Agents
Ronald W.
Oppenheim1,
David
Prevette1,
Anselem
D'Costa1,
Siwei
Wang1,
Lucien J.
Houenou1, and
J. Michael
McIntosh2
1 Department of Neurobiology and Anatomy and the
Neuroscience Program, Wake Forest University Medical School,
Winston-Salem, North Carolina 27157, and 2 Departments of
Biology and Psychiatry, University of Utah, Salt Lake City, Utah
84112
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  -bungarotoxin (-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 -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.
Key words:
motoneurons; activity; cell death; nicotinic receptors; spinal cord; embryo; chicken; acetylcholine
Copyright © 2000 Society for Neuroscience 0270-6474/00/20166117-08$05.00/0
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