Impaired PtdIns(4,5)P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking

• Published in: Nature (London) 2004-09, Vol.431 (7007), p.415-422
• Main Authors: Paolo, Gilbert Di, Moskowitz, Howard S., Gipson, Keith, Wenk, Markus R., Voronov, Sergey, Obayashi, Masanori, Flavell, Richard, Fitzsimonds, Reiko M., Ryan, Timothy A., Camilli, Pietro De
• Format: Article
• Language: English
• Subjects: Action Potentials; Animals; Biological and medical sciences; Biological Transport; Cells, Cultured; Clathrin - metabolism; Electric Conductivity; Endocytosis; Exocytosis; Fundamental and applied biological sciences. Psychology; Gene Deletion; Humanities and Social Sciences; Kinetics; Mice; Mice, Knockout; multidisciplinary; Neurons - cytology; Neurons - metabolism; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositol Phosphates - biosynthesis; Phosphatidylinositol Phosphates - metabolism; Phosphotransferases (Alcohol Group Acceptor) - deficiency; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Presynaptic Terminals - metabolism; Science; Science (multidisciplinary); Synaptic Transmission; Synaptic Vesicles - metabolism; Vertebrates: nervous system and sense organs
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature02896

Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P 2 ) has an important function in cell regulation both as a precursor of second messenger molecules and by means of its direct interactions with cytosolic and membrane proteins. Biochemical studies have suggested a role for PtdIns(4,5)P 2 in clathrin coat dynamics, and defects in its dephosphorylation at the synapse produce an accumulation of coated endocytic intermediates. However, the involvement of PtdIns(4,5)P 2 in synaptic vesicle exocytosis remains unclear. Here, we show that decreased levels of PtdIns(4,5)P 2 in the brain and an impairment of its depolarization-dependent synthesis in nerve terminals lead to early postnatal lethality and synaptic defects in mice. These include decreased frequency of miniature currents, enhanced synaptic depression, a smaller readily releasable pool of vesicles, delayed endocytosis and slower recycling kinetics. Our results demonstrate a critical role for PtdIns(4,5)P 2 synthesis in the regulation of multiple steps of the synaptic vesicle cycle.