Phospholipids (PLs) are asymmetrically distributed at the plasma membrane. This asymmetric lipid distribution is transiently altered during calcium-regulated exocytosis, but the impact of this transient remodeling on presynaptic function is currently unknown. As phospholipid scramblase 1 (PLSCR1) randomizes PL distribution between the two leaflets of the plasma membrane in response to calcium activation, we set out to determine its role in neurotransmission. We report here that PLSCR1 is expressed in cerebellar granule cells (GrCs) and that PLSCR1-dependent phosphatidylserine egress occurred at synapses in response to neuron stimulation. Synaptic transmission is impaired at GrC Plscr1^–/– synapses, and both PS egress and synaptic vesicle (SV) endocytosis are inhibited in Plscr1^–/– cultured neurons from male and female mice, demonstrating that PLSCR1 controls PL asymmetry remodeling and SV retrieval following neurotransmitter release. Altogether, our data reveal a novel key role for PLSCR1 in SV recycling and provide the first evidence that PL scrambling at the plasma membrane is a prerequisite for optimal presynaptic performance.

磷脂（PL）不对称地分布在质膜上。这种不对称的脂质分布在钙调节的胞吐作用期间短暂改变，但这种短暂重塑对突触前功能的影响目前尚不清楚。由于磷脂扰乱酶 1 (PLSCR1) 响应钙激活而随机化质膜两个小叶之间的 PL 分布，因此我们着手确定其在神经传递中的作用。我们在此报告，PLSCR1 在小脑颗粒细胞 (GrC) 中表达，并且响应神经元刺激，突触处发生 PLSCR1 依赖性磷脂酰丝氨酸流出。 GrC Plscr1 ^–/–突触处的突触传递受损，并且Plscr1 ^–/–培养的雄性和雌性小鼠神经元中 PS 出口和突触小泡 (SV) 内吞作用均受到抑制，表明 PLSCR1 控制神经递质后的 PL 不对称重塑和 SV 恢复发布。总而言之，我们的数据揭示了 PLSCR1 在 SV 回收中的新关键作用，并提供了第一个证据，证明质膜上的 PL 扰乱是最佳突触前性能的先决条件。