Essential role of phosphoinositide metabolism in synaptic vesicle recycling.
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.
Cremona
O
O
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Di Paolo
G
G
Wenk
M R
MR
Lüthi
A
A
Kim
W T
WT
Takei
K
K
Daniell
L
L
Nemoto
Y
Y
Shears
S B
SB
Flavell
R A
RA
McCormick
D A
DA
De Camilli
P
P
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
D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D010716:Phosphatidylinositols; C097702:synaptojanin; D010744:Phosphoric Monoester Hydrolases