PICK1 Controls Activity-Dependent Synaptic Vesicle Cargo Retrieval

Abstract

Efficient retrieval of synaptic vesicles (SVs) is crucial to sustain synaptic transmission. PICK1 is a unique PDZ- and BAR-domain-containing protein that regulates the trafficking of postsynaptic glutamate receptors. It is also expressed in presynaptic terminals and is associated with the SVs; however, its role in regulating SV recycling remains unknown. Here we show that PICK1 loss of function selectively slows the kinetics of SV endocytosis in primary hippocampal neurons during high-frequency stimulation. PICK1 knockdown also causes surface stranding and mislocalization of the major SV protein synaptophysin along the axon. A functional PDZ domain of PICK1 and its interaction with the core endocytic protein AP-2 are required for the proper targeting and clustering of synaptophysin. We further show that PICK1, and its interaction with AP-2, are required for efficient SV endocytosis and sustained glutamate release. Our findings therefore identify PICK1 as a key regulator of presynaptic vesicle recycling in central synapses.