Regulation of synaptic plasticity and synaptic vesicle dynamics by the PDZ protein Scribble

The Drosophila tumor suppressor Scribble (Scrib) is a PDZ-containing protein required for maintaining epithelial cell polarity. At the larval neuromuscular junction, Scrib colocalizes and indirectly interacts with another tumor suppressor and PDZ protein, Discs-Large (Dlg). Previous studies demonstrate that Dlg is critical for development of normal synapse structure and function, as well as for normal synaptic Scrib localization. Here we show that Scrib is also an important regulator of synaptic architecture and physiology. The most notable ultrastructural defect in scrib mutants is an increase in the number of synaptic vesicles in an area of the synaptic bouton thought to contain the reserve vesicle pool. Additionally, the number of active zones is reduced in scrib mutants. Functionally, the scrib synapse behaves relatively normally at low-frequency stimulation. However, several forms of plasticity at this synapse are drastically altered in the mutants. Specifically, scrib mutants exhibit loss of facilitation and post-tetanic potentiation, and faster synaptic depression. In addition, FM1-43 imaging of recycling synaptic vesicles shows that vesicle dynamics are impaired in scrib mutants. These results identify Scrib as an essential regulator of short-term synaptic plasticity. Taken together, our results are consistent with a model in which Scrib is required to sustain synaptic vesicle concentrations at their sites of release.