title: Essential role of phosphoinositide metabolism in synaptic vesicle recycling.
abstract: Growing evidence suggests that phosphoinositides play an important role in membrane traffic. A polyphosphoinositide phosphatase, synaptojanin 1, was identified as a major presynaptic protein associated with endocytic coated intermediates. We report here that synaptojanin 1-deficient mice exhibit neurological defects and die shortly after birth. In neurons of mutant animals, PI(4,5)P2 levels are increased, and clathrin-coated vesicles accumulate in the cytomatrix-rich area that surrounds the synaptic vesicle cluster in nerve endings. In cell-free assays, reduced phosphoinositide phosphatase activity correlated with increased association of clathrin coats with liposomes. Intracellular recording in hippocampal slices revealed enhanced synaptic depression during prolonged high-frequency stimulation followed by delayed recovery. These results provide genetic evidence for a crucial role of phosphoinositide metabolism in synaptic vesicle recycling.
authors.affiliation: Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: O
authors.initials: O
authors.lastname: Cremona
authors.forename: G
authors.initials: G
authors.lastname: Di Paolo
authors.forename: M R
authors.initials: MR
authors.lastname: Wenk
authors.forename: A
authors.initials: A
authors.lastname: Lüthi
authors.forename: W T
authors.initials: WT
authors.lastname: Kim
authors.forename: K
authors.initials: K
authors.lastname: Takei
authors.forename: L
authors.initials: L
authors.lastname: Daniell
authors.forename: Y
authors.initials: Y
authors.lastname: Nemoto
authors.forename: S B
authors.initials: SB
authors.lastname: Shears
authors.forename: R A
authors.initials: RA
authors.lastname: Flavell
authors.forename: D A
authors.initials: DA
authors.lastname: McCormick
authors.forename: P
authors.initials: P
authors.lastname: De Camilli
mesh_terms: D000818:Animals; D002474:Cell-Free System; D002540:Cerebral Cortex / Q000378:metabolism; D003034:Coated Pits, Cell-Membrane / Q000378:metabolism; D004705:Endocytosis; D004791:Enzyme Inhibitors / Q000378:metabolism; D005091:Exons; D006624:Hippocampus / Q000502:physiology*; D066298:In Vitro Techniques; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009411:Nerve Endings / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D010716:Phosphatidylinositols / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D010716:Phosphatidylinositols; C097702:synaptojanin; D010744:Phosphoric Monoester Hydrolases