The vesicular glutamate transporter VGLUT3 synergizes striatal acetylcholine tone

Nat Neurosci. 2008 Mar;11(3):292-300. doi: 10.1038/nn2052. Epub 2008 Feb 17.


Three subtypes of vesicular transporters accumulate glutamate into synaptic vesicles to promote its vesicular release. One of the subtypes, VGLUT3, is expressed in neurons, including cholinergic striatal interneurons, that are known to release other classical transmitters. Here we showed that disruption of the Slc17a8 gene (also known as Vglut3) caused an unexpected hypocholinergic striatal phenotype. Vglut3(-/-) mice were more responsive to cocaine and less prone to haloperidol-induced catalepsy than wild-type littermates, and acetylcholine release was decreased in striatum slices lacking VGLUT3. These phenotypes were associated with a colocalization of VGLUT3 and the vesicular acetylcholine transporter (VAChT) in striatal synaptic vesicles and the loss of a synergistic effect of glutamate on vesicular acetylcholine uptake. We propose that this vesicular synergy between two transmitters is the result of the unbalanced bioenergetics of VAChT, which requires anion co-entry for continuing vesicular filling. Our study reveals a previously unknown effect of glutamate on cholinergic synapses with potential functional and pharmacological implications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / biosynthesis
  • Acetylcholine / metabolism*
  • Amino Acid Transport Systems, Acidic / genetics
  • Amino Acid Transport Systems, Acidic / metabolism*
  • Animals
  • Antipsychotic Agents / pharmacology
  • Corpus Striatum / metabolism*
  • Dopamine Uptake Inhibitors / pharmacology
  • Down-Regulation / genetics
  • Drug Resistance / genetics
  • Glutamic Acid / metabolism*
  • Interneurons / metabolism
  • Mice
  • Mice, Knockout
  • Motor Activity / genetics
  • Organ Culture Techniques
  • Presynaptic Terminals / drug effects
  • Presynaptic Terminals / metabolism*
  • Rats
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / genetics*
  • Synaptic Vesicles / metabolism
  • Vesicular Acetylcholine Transport Proteins / metabolism


  • Amino Acid Transport Systems, Acidic
  • Antipsychotic Agents
  • Dopamine Uptake Inhibitors
  • Slc18a3 protein, mouse
  • Vesicular Acetylcholine Transport Proteins
  • vesicular glutamate transporter 3, mouse
  • Glutamic Acid
  • Acetylcholine