Modulation of presynaptic actin dynamics is fundamental to synaptic growth and functional plasticity; yet the underlying molecular and cellular mechanisms remain largely unknown. At Drosophila NMJs, the presynaptic Rac1-SCAR pathway mediates BMP-induced receptor macropinocytosis to inhibit BMP growth signaling. Here, we show that the Rho-type GEF Vav acts upstream of Rac1 to inhibit synaptic growth through macropinocytosis. We also present evidence that Vav-Rac1-SCAR signaling has additional roles in tetanus-induced synaptic plasticity. Presynaptic inactivation of Vav signaling pathway components, but not regulators of macropinocytosis, impairs post-tetanic potentiation (PTP) and enhances synaptic depression depending on external Ca2+ concentration. Interfering with the Vav-Rac1-SCAR pathway also impairs mobilization of reserve pool (RP) vesicles required for tetanus-induced synaptic plasticity. Finally, treatment with an F-actin–stabilizing drug completely restores RP mobilization and plasticity defects in Vav mutants. We propose that actin-regulatory Vav-Rac1-SCAR signaling independently regulates structural and functional presynaptic plasticity by driving macropinocytosis and RP mobilization, respectively.

中文翻译：

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Vav 通过独特的基于肌动蛋白的过程独立调节突触生长和可塑性

突触前肌动蛋白动力学的调节是突触生长和功能可塑性的基础；然而，潜在的分子和细胞机制仍然很大程度上未知。在果蝇 NMJ 中，突触前 Rac1-SCAR 通路介导 BMP 诱导的受体巨胞饮作用，从而抑制 BMP 生长信号传导。在这里，我们发现 Rho 型 GEF Vav 在 Rac1 上游发挥作用，通过巨胞饮作用抑制突触生长。我们还提供证据表明 Vav-Rac1-SCAR 信号在破伤风诱导的突触可塑性中具有额外的作用。 Vav 信号通路成分的突触前失活（但不是巨胞饮作用的调节因子）会损害破伤风后增强 (PTP)，并根据外部 Ca2+ 浓度增强突触抑制。干扰 Vav-Rac1-SCAR 通路还会损害破伤风诱导的突触可塑性所需的储备库 (RP) 囊泡的动员。最后，用 F-肌动蛋白稳定药物治疗可以完全恢复 Vav 突变体的 RP 动员和可塑性缺陷。我们提出，肌动蛋白调节的 Vav-Rac1-SCAR 信号分别通过驱动巨胞饮作用和 RP 动员来独立调节突触前的结构和功能可塑性。