Department of Neuroscience, Cell Biology, and Physiology, Wright State University, Dayton, Ohio 45435.
George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT 84108, and.
J Neurosci. 2018 Feb 14;38(7):1725-1736. doi: 10.1523/JNEUROSCI.1789-17.2018. Epub 2018 Jan 11.
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 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. 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.
神经肌肉接头 (NMJ) 处的神经递质受体阻断已被证明可引发释放的突触小泡数量增加（量子含量，QC），这种反应称为同型突触可塑性。这种可塑性的机制尚不清楚。在这里，我们使用选择性毒素证明，NMJ 处的 α1 包含型烟碱型乙酰胆碱受体 (nAChR) 的阻断会引发 QC 的上调。通过具有拮抗剂活性的药物诱导的 nAChR 电流减少表明，突触电流减少不会引发 QC 的上调。这些数据得出了一个惊人的结论，即突触传递的中断不会被感知为触发 QC 的上调。在研究 nAChR 的部分阻断对 QC 的影响时，我们观察到微小突触电流衰减动力学的微小但可重复的增加。动力学的变化与 QC 的增加相关，这增加了突触后 nAChR 构象变化可能与突触前 QC 增加相关的可能性。我们提出，除了在突触传递中发挥作用外，离子型肌肉烟碱型 nAChR 还可以作为参与突触可塑性的信号分子。由于 nAChR 已被牵连到多种疾病状态，因此 nAChR 可能参与触发突触可塑性的发现可能具有广泛的影响。启动神经系统突触可塑性的信号仍然不完全清楚。我们使用小鼠神经肌肉接头作为模型突触，研究了如何感知神经递质受体阻断以触发突触可塑性。我们的研究得出了一个令人惊讶的结论，即突触电流的变化或突触前或突触后细胞的尖峰都不会被感知为启动突触可塑性。相反，除了在突触传递中发挥作用外，突触后烟碱型乙酰胆碱受体 (nAChR) 还可以作为信号分子触发突触可塑性。由于 nAChR 已被牵连到多种疾病状态，因此它们可能介导突触可塑性的发现具有广泛的意义。
