Department of Anatomy and Cell Biology, University of Iowa, Iowa City, United States.
Department of Human Medicine, Carl-von-Ossietzky University Oldenburg, Oldenburg, Germany.
Elife. 2022 Oct 10;11:e81505. doi: 10.7554/eLife.81505.
Synapses contain a limited number of synaptic vesicles (SVs) that are released in response to action potentials (APs). Therefore, sustaining synaptic transmission over a wide range of AP firing rates and timescales depends on SV release and replenishment. Although actin dynamics impact synaptic transmission, how presynaptic regulators of actin signaling cascades control SV release and replenishment remains unresolved. Rac1, a Rho GTPase, regulates actin signaling cascades that control synaptogenesis, neuronal development, and postsynaptic function. However, the presynaptic role of Rac1 in regulating synaptic transmission is unclear. To unravel Rac1's roles in controlling transmitter release, we performed selective presynaptic ablation of Rac1 at the mature mouse calyx of Held synapse. Loss of Rac1 increased synaptic strength, accelerated EPSC recovery after conditioning stimulus trains, and augmented spontaneous SV release with no change in presynaptic morphology or AZ ultrastructure. Analyses with constrained short-term plasticity models revealed faster SV priming kinetics and, depending on model assumptions, elevated SV release probability or higher abundance of tightly docked fusion-competent SVs in Rac1-deficient synapses. We conclude that presynaptic Rac1 is a key regulator of synaptic transmission and plasticity mainly by regulating the dynamics of SV priming and potentially SV release probability.
突触包含数量有限的突触小泡 (SVs)，这些小泡在动作电位 (APs) 响应时被释放。因此，维持广泛的 AP 发射率和时间尺度的突触传递取决于 SV 的释放和补充。尽管肌动蛋白动力学会影响突触传递，但突触前肌动蛋白信号级联的调节因子如何控制 SV 的释放和补充仍未解决。Rac1 是一种 Rho GTPase，它调节肌动蛋白信号级联，控制突触发生、神经元发育和突触后功能。然而，Rac1 在调节突触传递中的突触前作用尚不清楚。为了解开 Rac1 在控制递质释放中的作用，我们在成熟的小鼠耳窝大突触上选择性地进行了 Rac1 的突触前消融。Rac1 的缺失增加了突触强度，加速了条件刺激训练后的 EPSC 恢复，并且增加了自发性 SV 释放，而突触前形态或 AZ 超微结构没有变化。受约束的短期可塑性模型分析显示，SV 引发动力学更快，并且根据模型假设，在 Rac1 缺陷型突触中，SV 释放概率升高或紧密对接的融合相容 SV 数量增加。我们的结论是，突触前 Rac1 是突触传递和可塑性的关键调节因子，主要通过调节 SV 引发的动力学和潜在的 SV 释放概率来调节。
