The ability of presynaptic dopamine terminals to tune neurotransmitter release to meet the
demands of neuronal activity is critical to neurotransmission. Although vesicle content has been
assumed to be static, in vitro data increasingly suggest that cell activity modulates vesicle
content. Freyberg and colleagues use a coordinated genetic, pharmacological, and imaging approach in Drosophila to study the presynaptic machinery responsible for these vesicular processes in vivo.
Freyberg and colleagues show that cell depolarization increases synaptic vesicle dopamine content prior to release via vesicular hyperacidification. This depolarization-induced hyperacidification is mediated by
the vesicular glutamate transporter (VGLUT). Remarkably, both depolarization-induced
dopamine vesicle hyperacidification and its dependence on VGLUT2 are seen in ventral
midbrain dopamine neurons in the mouse. Together, these data suggest that in response to
depolarization, dopamine vesicles utilize a cascade of vesicular transporters to dynamically
increase the vesicular pH gradient, thereby increasing dopamine vesicle content.