Zinc Dynamics and Action at Excitatory Synapses
Zinc Dynamics and Action at Excitatory Synapses
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DOI：
10.1016/j.neuron.2014.04.034
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发表时间：
2014-06-04
期刊：
影响因子：
16.2
通讯作者：
Paoletti, Pierre
中科院分区：
文献类型：
--
作者：
Vergnano, Angela Maria;Rebola, Nelson;Paoletti, Pierre
在发现锌离子在突触囊泡中以高水平存在几十年后，在突触活动期间锌在何处、何时以及释放多少仍然存在很大争议。在这里，我们提供了一个定量评估锌的动态突触间隙，并澄清其在调节兴奋性神经传递的作用相结合的突触记录缺乏锌信号与Monte Carlo模拟。周围的细胞外锌水平太低，无法对NMDA受体（NMDAR）上的GluN 2A特异性纳摩尔锌位点进行紧张性占据。然而，在短时间的生理相关突触刺激后，锌在间隙中短暂升高并选择性抑制突触后GluN 2A-NMDAR，导致突触整合和可塑性的变化。我们的工作建立了锌的作用规则，并揭示了锌的调制超出海马苔藓纤维兴奋性SC-CA 1突触。通过特异性调节GluN 2A-NMDAR信号，锌作为神经元回路的广泛活性依赖性调节剂。
Decades after the discovery that ionic zinc is present at high levels in glutamatergic synaptic vesicles, where, when, and how much zinc is released during synaptic activity remains highly controversial. Here we provide a quantitative assessment of zinc dynamics in the synaptic cleft and clarify its role in the regulation of excitatory neurotransmission by combining synaptic recordings from mice deficient for zinc signaling with Monte Carlo simulations. Ambient extracellular zinc levels are too low for tonic occupation of the GluN2A-specific nanomolar zinc sites on NMDA receptors (NMDARs). However, following short trains of physiologically relevant synaptic stimuli, zinc transiently rises in the cleft and selectively inhibits postsynaptic GluN2A-NMDARs, causing changes in synaptic integration and plasticity. Our work establishes the rules of zinc action and reveals that zinc modulation extends beyond hippocampal mossy fibers to excitatory SC-CA1 synapses. By specifically moderating GluN2A-NMDAR signaling, zinc acts as a widespread activity-dependent regulator of neuronal circuits.