The coordination of synaptic vesicle exocytosis and endocytosis supports neurotransmitter release from presynaptic terminals. Although inositol pyrophosphates, such as 5-diphosphoinositol pentakisphosphate (5-IP₇), are versatile signaling metabolites in many biological events, physiological actions of 5-IP₇ on synaptic membrane vesicle trafficking remain unclear. Here, we investigated the role of 5-IP₇ in synaptic transmission in hippocampal brain slices from inositol hexakisphosphate kinase 1 (Ip6k1)-knockout mice. We found that presynaptic release probability was significantly increased in Ip6k1-knockout neurons, implying enhanced activity-dependent synaptic vesicle exocytosis. Expression of wild-type but not catalytically inactive IP6K1 in the Ip6k1-knockout hippocampus restored the altered presynaptic release probability. Moreover, Ip6k1-knockout neurons were insensitive to folimycin, a vacuolar ATPase inhibitor, and dynasore, a dynamin inhibitor, suggesting marked impairment in synaptic endocytosis during exocytosis. Our findings collectively establish that IP6K1 and its product, 5-IP₇, act as key physiological determinants for inhibition of presynaptic vesicle exocytosis and stimulation of endocytosis at central synapses.

突触小泡胞吐作用和内吞作用的协调支持神经递质从突触前末端的释放。尽管肌醇焦磷酸盐，例如5-二磷酸肌醇五磷酸（5-IP ₇）在许多生物学事件中是通用的信号代谢物，但5-IP ₇对突触膜囊泡运输的生理作用仍然不清楚。在这里，我们研究了5-IP ₇在肌醇六磷酸磷酸激酶1（Ip6k1）敲除小鼠海马脑片突触传递中的作用。我们发现，Ip6k1突触前释放的可能性明显增加-敲除神经元，暗示增强的活动依赖性突触小泡胞吐作用。在Ip6k1基因敲除的海马中表达野生型而非非催化活性IP6K1可以恢复突触前释放的可能性。此外，Ip6k1敲除神经元对液泡ATPase抑制剂叶霉素和动力抑制剂dynasore不敏感，表明胞吐过程中突触内吞作用明显受损。我们的发现共同证明，IP6K1及其产物5-IP ₇是抑制突触前囊泡胞吐作用和刺激中央突触内吞作用的关键生理决定因素。