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 i dentified as a major presynaptic protein associated with endocytic coated i ntermediates. We report here that synaptojanin 1-deficient mice exhibit neu rological defects and die shortly after birth. In neurons of mutant animals , PI(4,5)beta(2) levels are increased, and clathrin-coated vesicles accumul ate in the cytomatrix-rich area that surrounds the synaptic vesicle cluster in nerve endings. In cell-free assays, reduced phosphoinositide phosphatas e activity correlated with increased association of clathrin coats with lip osomes. Intracellular recording in hippocampal slices revealed enhanced syn aptic depression during prolonged high-frequency stimulation followed by de layed recovery. These results provide genetic evidence far a crucial role o f phosphoinositide metabolism in synaptic vesicle recycling.