Centre for Research in Neuroscience, Brain Repair and Integrative Neuroscience Programme, Department of Neurology and Neurosurgery, The Research Institute of the McGill University Health Centre, Montreal General Hospital, Montreal, QC H3G 1A4, Canada.
Centre for Research in Neuroscience, Brain Repair and Integrative Neuroscience Programme, Department of Neurology and Neurosurgery, The Research Institute of the McGill University Health Centre, Montreal General Hospital, Montreal, QC H3G 1A4, Canada; Integrated Program in Neuroscience, McGill University, 3801 University Street, Montreal, QC H3A 2B4, Canada.
Neuron. 2017 Nov 15;96(4):839-855.e5. doi: 10.1016/j.neuron.2017.09.030. Epub 2017 Oct 12.
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, Mg-sensitive preNMDAR signaling upregulates replenishment of the readily releasable vesicle pool during high-frequency firing. In conditional RIM1αβ deletion mice, preNMDAR upregulation of vesicle replenishment was abolished, yet preNMDAR control of spontaneous release was unaffected. Conversely, JNK2 blockade prevented Mg-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. VIDEO ABSTRACT.
突触前 NMDA 受体（preNMDAR）控制着突触释放，但人们对其具体机制还不太了解。Rab3 相互作用分子（RIMs）在突触前活性区提供支架，并参与囊泡引发。此外，c-Jun N 端激酶（JNK）已被牵涉到调节自发性释放。我们证明，在发育中的小鼠视觉皮层的连接的第 5 层锥体神经元对中，Mg 敏感的 preNMDAR 信号在高频放电过程中上调易释放囊泡池的补充。在条件性 RIM1αβ 缺失小鼠中，preNMDAR 对囊泡补充的上调作用被消除，但 preNMDAR 对自发性释放的控制不受影响。相反，JNK2 阻断阻止了 Mg 不敏感的 preNMDAR 信号调节自发性释放，但 preNMDAR 对诱发释放的控制仍然完整。因此，我们发现 preNMDAR 通过独立且不重叠的机制，以不同的方式信号来控制诱发和自发性释放。我们的研究结果表明，preNMDAR 有时可能通过代谢型信号传导，并支持诱发和自发性释放是不同过程的新兴原则。视频摘要。
