Neurotransmission at synapses is mediated by the fusion and subsequent endocytosis of synaptic vesicle membranes. Actin has been suggested to be required for presynaptic endocytosis but the mechanisms that control actin polymerization and its mode of action within presynaptic nerve terminals remain poorly understood. We combine optical recordings of presynaptic membrane dynamics and ultrastructural analysis with genetic and pharmacological manipulations to demonstrate that presynaptic endocytosis is controlled by actin regulatory diaphanous-related formins mDia1/3 and Rho family GTPase signaling in mouse hippocampal neurons. We show that impaired presynaptic actin assembly in the near absence of mDia1/3 and reduced RhoA activity is partly compensated by hyperactivation of Rac1. Inhibition of Rac1 signaling further aggravates impaired presynaptic endocytosis elicited by loss of mDia1/3. Our data suggest that interdependent mDia1/3-Rho and Rac1 signaling pathways cooperatively act to facilitate synaptic vesicle endocytosis by controlling presynaptic F-actin.

中文翻译：

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Rho GTPase 信号传导和 mDia 通过突触前肌动蛋白促进内吞作用

突触的神经传递是由突触小泡膜的融合和随后的内吞作用介导的。肌动蛋白被认为是突触前内吞作用所必需的，但控制肌动蛋白聚合的机制及其在突触前神经末梢内的作用模式仍然知之甚少。我们将突触前膜动力学的光学记录和超微结构分析与遗传和药理学操作相结合，证明突触前内吞作用是由小鼠海马神经元中肌动蛋白调节透明相关的 formins mDia1/3 和 Rho 家族 GTPase 信号传导控制的。我们发现，在 mDia1/3 几乎缺失和 RhoA 活性降低的情况下，突触前肌动蛋白组装受损，可以通过 Rac1 的过度激活部分补偿。Rac1 信号传导的抑制进一步加剧 mDia1/3 缺失引起的突触前内吞作用受损。我们的数据表明，相互依赖的 mDia1/3-Rho 和 Rac1 信号通路通过控制突触前 F-肌动蛋白协同作用，促进突触小泡内吞作用。