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PICK1 Controls Activity-Dependent Synaptic Vesicle Cargo Retrieval

2020; Cell Press; Volume: 33; Issue: 4 Linguagem: Inglês

10.1016/j.celrep.2020.108312

2639-1856

Xuan Ling Hilary Yong, Michael A. Cousin, Victor Anggono,

Neuroscience and Neuropharmacology Research

Efficient retrieval of synaptic vesicles (SVs) is crucial to sustain synaptic transmission. Protein interacting with C-kinase 1 (PICK1) is a unique PDZ (postsynaptic density-95/disc-large/zona-occluden-1)- and BAR (Bin-Amphiphysin-Rvs )-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 major SV proteins, synaptophysin and vGlut1, along the axon. A functional PDZ domain of PICK1 and its interaction with the core endocytic adaptor protein (AP)-2 are required for the proper targeting and clustering of synaptophysin. Furthermore, 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.