Interplay between VGLUT Isoforms and Endophilin A1 Regulates Neurotransmitter Release and Short-Term Plasticity

Vesicular glutamate transporters (VGLUTs) are essential for filling synaptic vesicles with glutamate and mammals express three VGLUT isoforms (VGLUT1–3) with distinct spatiotemporal expression patterns. Here, we find that neurons expressing VGLUT1 have lower release probability and less short-term depression than neurons expressing VGLUT2 or VGLUT3. Investigation of the underlying mechanism identified endophilin A1 as a positive regulator of exocytosis whose expression levels are positively correlated with release efficiency and showed that the differences in release efficiency between VGLUT1- and VGLUT2-expressing neurons are due to VGLUT1's ability to bind endophilin A1 and inhibit endophilin-induced enhancement of release probability. [Display omitted] ► Neurons expressing VGLUT1 have lower release probability than neurons with VGLUT2/3 ► VGLUT3 expression is sufficient for glutamate release in GABAergic striatal neurons ► Endophilin A1 expression levels positively correlate with release probability ► VGLUT1 binding to endophilin inhibits endophilin's enhancement of exocytosis