Differential Regulation of Evoked and Spontaneous Release by Presynaptic NMDA Receptors
Differential Regulation of Evoked and Spontaneous Release by Presynaptic NMDA Receptors
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DOI：
10.1016/j.neuron.2017.09.030
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发表时间：
2017-11-15
期刊：
影响因子：
16.2
通讯作者：
Sjostrom, Per Jesper
中科院分区：
文献类型：
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作者：
Abrahamsson, Therese;Chou, Christina You Chien;Sjostrom, Per Jesper
突触前NMDA受体(PreNMDAR)控制突触的释放，但其机制尚不清楚。Rab3相互作用分子(RIMS)在突触前活动区提供支架，并参与囊泡启动。此外，c-Jun氨基末端激酶(JNK)参与了自发释放的调节。我们证明，在发育中的小鼠视皮层的连接的第5层锥体细胞对，镁敏感的前NMDAR信号在高频放电过程中上调了容易释放的囊泡池的补充。在条件性RIM1αβ缺失小鼠中，前NMDAR对囊泡补充的上调作用被取消，但对自发释放的前NMDAR控制没有影响。相反，JNK2阻断阻止了对镁离子不敏感的前NMDAR信号调节自发释放，但前NMDAR对诱发释放的控制保持不变。因此，我们发现前NMDARs通过独立和非重叠的机制来差异化地控制诱发和自发释放。我们的发现表明，前NMDAR有时可能是代谢信号，并支持新出现的原理，即诱发释放和自发释放是不同的过程。
Presynaptic NMDA receptors (preNMDARs) control synaptic release, but it is not well understood how. Rab3-interacting molecules (RIMs) provide scaffolding at presynaptic active zones and are involved in vesicle priming. Moreover, c-Jun N-terminal kinase (JNK) has been implicated in regulation of spontaneous release. We demonstrate that, at connected layer 5 pyramidal cell pairs of developing mouse visual cortex, Mg2+-sensitive preNMDAR signaling upregulates replenishment of the readily releasable vesicle pool during high-frequency firing. In conditional RIM1 alpha beta deletion mice, preNMDAR upregulation of vesicle replenishment was abolished, yet preNMDAR control of spontaneous release was unaffected. Conversely, JNK2 blockade prevented Mg2+-insensitive preNMDAR signaling from regulating spontaneous release, but preNMDAR control of evoked release remained intact. We thus discovered that preNMDARs signal differentially to control evoked and spontaneous release by independent and non-overlapping mechanisms. Our findings suggest that preNMDARs may sometimes signal metabotropically and support the emerging principle that evoked and spontaneous release are distinct processes.