Essential Role of Phosphoinositide Metabolism in Synaptic Vesicle Recycling

TLDR

Phosphoinositides are key regulators of membrane traffic, and the presynaptic phosphatase synaptojanin 1 is a major component of endocytic coated intermediates. Synaptojanin 1 deficiency causes early lethality, elevated PI(4,5)P2, accumulation of clathrin‑coated vesicles, impaired synaptic vesicle recycling, and heightened synaptic depression during high‑frequency stimulation, underscoring the 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.