Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University Medical School, Stanford, CA, USA.
EMBO J. 2020 Apr 1;39(7):e103208. doi: 10.15252/embj.2019103208. Epub 2020 Mar 5.
To achieve ultrafast neurotransmission, neurons assemble synapses with highly organized presynaptic and postsynaptic nanomachines that are aligned by synaptic adhesion molecules. How functional assembly of presynaptic active zones is controlled via trans-synaptic interactions remains unknown. Here, we conditionally deleted all three neurexin adhesion molecules from presynaptic neurons of the calyx of Held in the mouse auditory system, a model synapse that allows precise biophysical analyses of synaptic properties. The pan-neurexin deletion had no effect on synapse development or the basic release machinery, but dramatically impaired fast neurotransmitter release. The overall properties of presynaptic calcium ion channels appeared normal, as reflected by the similar characteristics of calcium currents recorded at the nerve terminals. However, the pan-neurexin deletion significantly impaired the tight coupling of calcium influx to exocytosis, thereby suppressing neurotransmitter release. Furthermore, the pan-neurexin deletion reduced the function of calcium-activated BK potassium channels, whose activation depends on their tight association with presynaptic calcium channels. Together, these results suggest that neurexins perform a major function at the calyx synapse in coupling presynaptic calcium channels to release sites.
为了实现超快速的神经传递，神经元通过突触黏附分子将具有高度组织化的突触前和突触后纳米机器组装成突触。通过突触间相互作用来控制突触前活性区的功能性组装的机制尚不清楚。在这里，我们在小鼠听觉系统的蜗轴中条件性地删除了所有三种神经连接素黏附分子，这是一个模型突触，可以对突触特性进行精确的生物物理分析。全神经连接素缺失对突触发育或基本释放机制没有影响，但显著损害了快速神经递质的释放。突触前钙离子通道的整体特性似乎正常，这反映在神经末梢记录的钙电流的相似特征上。然而，全神经连接素缺失显著损害了钙离子内流与胞吐作用的紧密偶联，从而抑制了神经递质的释放。此外，全神经连接素缺失降低了钙激活的 BK 钾通道的功能，其激活依赖于它们与突触前钙离子通道的紧密结合。总之，这些结果表明神经连接素在蜗轴突触中发挥主要作用，将突触前钙离子通道与释放位点偶联。
