Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
Neuron. 2013 Jul 10;79(1):82-96. doi: 10.1016/j.neuron.2013.05.011. Epub 2013 Jun 13.
Short-term synaptic plasticity, the dynamic alteration of synaptic strength during high-frequency activity, is a fundamental characteristic of all synapses. At the calyx of Held, repetitive activity eventually results in short-term synaptic depression, which is in part due to the gradual exhaustion of releasable synaptic vesicles. This is counterbalanced by Ca(2+)-dependent vesicle replenishment, but the molecular mechanisms of this replenishment are largely unknown. We studied calyces of Held in knockin mice that express a Ca(2+)-Calmodulin insensitive Munc13-1(W464R) variant of the synaptic vesicle priming protein Munc13-1. Calyces of these mice exhibit a slower rate of synaptic vesicle replenishment, aberrant short-term depression and reduced recovery from synaptic depression after high-frequency stimulation. Our data establish Munc13-1 as a major presynaptic target of Ca(2+)-Calmodulin signaling and show that the Ca(2+)-Calmodulin-Munc13-1 complex is a pivotal component of the molecular machinery that determines short-term synaptic plasticity characteristics.
短期突触可塑性是高频活动期间突触强度的动态变化，是所有突触的基本特征。在 Held 神经球中，重复活动最终导致短期突触抑制，这部分是由于可释放的突触小泡逐渐耗尽。这被 Ca(2+)-依赖性囊泡补充所平衡，但这种补充的分子机制在很大程度上是未知的。我们研究了在表达突触囊泡引发蛋白 Munc13-1 的 Ca(2+)-钙调蛋白不敏感 W464R 变异体的敲入小鼠中的 Held 神经球。这些小鼠的神经球表现出较慢的突触囊泡补充速度、异常的短期抑制以及在高频刺激后从突触抑制中恢复的能力降低。我们的数据将 Munc13-1 确立为 Ca(2+)-钙调蛋白信号的主要突触前靶标，并表明 Ca(2+)-钙调蛋白-Munc13-1 复合物是决定短期突触可塑性特征的分子机制的关键组成部分。
