摘要：SummaryThe 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-IP7on synaptic membrane vesicle trafficking remain unclear. Here, we investigated the role of 5-IP7in synaptic transmission in hippocampal brain slices from inositol hexakisphosphate kinase 1 (Ip6k1)-knockout mice. We found that presynaptic release probability was significantly increased inIp6k1-knockout neurons, implying enhanced activity-dependent synaptic vesicle exocytosis. Expression of wild-type but not catalytically inactive IP6K1 in theIp6k1-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.Graphical AbstractDisplay OmittedHighlights•Excitatory synaptic vesicle release is increased inIp6k1-KO hippocampal neurons•Wild-type IP6K1 restores presynaptic functions and plasticity of KO neurons•Catalytically inactive mutant IP6K1 fails to rescue defective presynaptic release•Synaptic endocytosis during exocytosis is severely impaired inIp6k1-KO neuronsNeurogenetics; Neuroscience; Cell Biology
