Presynaptic Rac1 controls synaptic strength through the regulation of synaptic vesicle priming.
Presynaptic Rac1 controls synaptic strength through the regulation of synaptic vesicle priming.
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DOI：
10.7554/elife.81505
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发表时间：
2022-10-10
期刊：
影响因子：
7.7
通讯作者：
Young SM Jr
中科院分区：
文献类型：
--
作者：
Keine C;Al-Yaari M;Radulovic T;Thomas CI;Valino Ramos P;Guerrero-Given D;Ranjan M;Taschenberger H;Kamasawa N;Young SM Jr
突触包含有限数量的突触囊泡（SV），其响应于动作电位（AP）而释放。因此，在大范围的AP放电率和时间尺度上维持突触传递取决于SV的释放和补充。虽然肌动蛋白动力学影响突触传递，如何突触前调节肌动蛋白信号级联控制SV的释放和补充仍然没有得到解决。Rac1是一种Rho GT3，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，Rac 1在调节突触传递中的突触前作用尚不清楚。为了阐明Rac1在控制递质释放中的作用，我们在成熟的小鼠Held突触萼进行了Rac1的选择性突触前消融。Rac 1的缺失增加了突触强度，加速了条件刺激后EPSC的恢复，增强了自发SV释放，而突触前形态学或AZ超微结构没有变化。与约束短期可塑性模型的分析显示，更快的SV启动动力学，并根据模型的假设，提高SV释放概率或更高丰度的紧密对接融合能力的SV在Rac1缺陷的突触。我们的结论是，突触前Rac1是一个关键的调节突触传递和可塑性，主要是通过调节SV启动和潜在的SV释放概率的动力学。
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.