Block of neurotransmitter receptors at the neuromuscular junction (NMJ) has been shown to trigger upregulation of the number of synaptic vesicles released (quantal content, QC), a response termed homeostatic synaptic plasticity. The mechanism underlying this plasticity is not known. Here, we used selective toxins to demonstrate that block of α1-containing nicotinic acetylcholine receptors (nAChRs) at the NMJ of male and female mice triggers the upregulation of QC. Reduction of current flow through nAChRs, induced by drugs with antagonist activity, demonstrated that reduction in synaptic current per se does not trigger upregulation of QC. These data led to the remarkable conclusion that disruption of synaptic transmission is not sensed to trigger upregulation of QC. During studies of the effect of partial block of nAChRs on QC, we observed a small but reproducible increase in the decay kinetics of miniature synaptic currents. The change in kinetics was correlated with the increase in QC and raises the possibility that a change in postsynaptic nAChR conformation may be associated with the presynaptic increase in QC. We propose that, in addition to functioning in synaptic transmission, ionotropic muscle nicotonic nAChRs may serve as signaling molecules that participate in synaptic plasticity. Because nAChRs have been implicated in a number of disease states, the finding that nAChRs may be involved in triggering synaptic plasticity could have wide-reaching implications.

SIGNIFICANCE STATEMENT The signals that initiate synaptic plasticity of the nervous system are still incompletely understood. Using the mouse neuromuscular junction as a model synapse, we studied how block of neurotransmitter receptors is sensed to trigger synaptic plasticity. Our studies led to the surprising conclusion that neither changes in synaptic current nor spiking of the presynaptic or postsynaptic cell are sensed to initiate synaptic plasticity. Instead, postsynaptic nicotinic acetylcholine receptors (nAChRs), in addition to functioning in synaptic transmission, may serve as signaling molecules that trigger synaptic plasticity. Because nAChRs have been implicated in a number of disease states, the finding that they may mediate synaptic plasticity has broad implications.

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