Traffic jam at the synapse: the defects in the clearance of transmitter release sites
  • Sunghoe Chang Ph.D.
  • SLS Colloquia / Sep 13th 04:00 pm / BLDG 110 ROOM N104
Abstract
 

Despite being highly abundant synaptic vesicle membrane protein and a candidate gene for autism, the physiological function of secretory carrier membrane protein 5 (SCAMP5) remains mostly unknown. Previously, we showed that reduced expression of SCAMP5 severely impaired synaptic vesicle (SV) endocytosis during stimulation and SCAMP5 functions specifically when the neuronal activity is high in which a heavy load on endocytosis was imposed during stimulus. Here, using optical imaging and electrophysiological experiments, we demonstrate that SCAMP5 plays a critical role in SV clearance from release sites during sustained neuronal activity. Truncation analysis revealed that the 2/3 loop domain of SCAMP5 flanked by two transmembrane domains is required for its interaction with adaptor protein 2 and clathrin heavy chain. Knockdown (KD) of SCAMP5 exhibited pronounced synaptic depression during high frequency stimulation and a slower recovery of the SV pool. These were attributed to strong frequency-dependent short-term depression of SV release caused by SCAMP5 KD-induced defects in release site clearance even under the condition of sufficient release-ready SVs. Super-resolution microscopy clearly proved the defects in SV clearance from the active zone by SCAMP5 KD. Thus, reduced expression of SCAMP5 impairs the efficiency of SV clearance, leading to traffic-jam at the active zone release sites, and subsequently causing aberrant short-term synaptic depression of synaptic release, which could represent a novel cellular mechanism of synaptic dysfunction observed in autism.