Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT

Neuron. 2017 Aug 30;95(5):1074-1088.e7. doi: 10.1016/j.neuron.2017.07.038. Epub 2017 Aug 17.


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. Here, we use a coordinated genetic, pharmacological, and imaging approach in Drosophila to study the presynaptic machinery responsible for these vesicular processes in vivo. We 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.

Keywords: VGLUT2; depolarization; dopamine; glutamate; neurotransmission; pH; presynaptic; synaptic vesicle; vesicle content.

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Dextroamphetamine / pharmacology
  • Dopamine / metabolism*
  • Drosophila
  • Drosophila Proteins / metabolism
  • Hydrogen-Ion Concentration
  • Locomotion / drug effects
  • Mesencephalon / metabolism
  • Mice
  • Neurons / metabolism*
  • Neurons / physiology
  • Presynaptic Terminals / metabolism
  • Synaptic Vesicles / metabolism*
  • Vesicular Glutamate Transport Protein 2 / genetics
  • Vesicular Glutamate Transport Protein 2 / physiology*


  • Drosophila Proteins
  • Vesicular Glutamate Transport Protein 2
  • Dextroamphetamine
  • Dopamine