title: Impaired PtdIns(4,5)P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking.
abstract: Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) 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)P2 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)P2 in synaptic vesicle exocytosis remains unclear. Here, we show that decreased levels of PtdIns(4,5)P2 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)P2 synthesis in the regulation of multiple steps of the synaptic vesicle cycle.
authors.affiliation: Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Di Paolo
authors.forename: Howard S
authors.initials: HS
authors.lastname: Moskowitz
authors.forename: Keith
authors.initials: K
authors.lastname: Gipson
authors.forename: Markus R
authors.initials: MR
authors.lastname: Wenk
authors.forename: Sergey
authors.initials: S
authors.lastname: Voronov
authors.forename: Masanori
authors.initials: M
authors.lastname: Obayashi
authors.forename: Richard
authors.initials: R
authors.lastname: Flavell
authors.forename: Reiko M
authors.initials: RM
authors.lastname: Fitzsimonds
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Ryan
authors.forename: Pietro
authors.initials: P
authors.lastname: De Camilli
mesh_terms: D000200:Action Potentials; D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D002966:Clathrin / Q000378:metabolism; D004553:Electric Conductivity; D004705:Endocytosis; D005089:Exocytosis; D017353:Gene Deletion; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates / Q000096:biosynthesis / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism*; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000378:metabolism*
chemical_list: D002966:Clathrin; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase