VGLUT3 (vesicular glutamate transporter type 3) contribution to the regulation of serotonergic transmission and anxiety

J Neurosci. 2010 Feb 10;30(6):2198-210. doi: 10.1523/JNEUROSCI.5196-09.2010.


Three different subtypes of H(+)-dependent carriers (named VGLUT1-3) concentrate glutamate into synaptic vesicles before its exocytotic release. Neurons using other neurotransmitter than glutamate (such as cholinergic striatal interneurons and 5-HT neurons) express VGLUT3. It was recently reported that VGLUT3 increases acetylcholine vesicular filling, thereby, stimulating cholinergic transmission. This new regulatory mechanism is herein designated as vesicular-filling synergy (or vesicular synergy). In the present report, we found that deletion of VGLUT3 increased several anxiety-related behaviors in adult and in newborn mice as early as 8 d after birth. This precocious involvement of a vesicular glutamate transporter in anxiety led us to examine the underlying functional implications of VGLUT3 in 5-HT neurons. On one hand, VGLUT3 deletion caused a significant decrease of 5-HT(1A)-mediated neurotransmission in raphe nuclei. On the other hand, VGLUT3 positively modulated 5-HT transmission of a specific subset of 5-HT terminals from the hippocampus and the cerebral cortex. VGLUT3- and VMAT2-positive serotonergic fibers show little or no 5-HT reuptake transporter. These results unravel the existence of a novel subset of 5-HT terminals in limbic areas that might play a crucial role in anxiety-like behaviors. In summary, VGLUT3 accelerates 5-HT transmission at the level of specific 5-HT terminals and can exert an inhibitory control at the raphe level. Furthermore, our results suggest that the loss of VGLUT3 expression leads to anxiety-associated behaviors and should be considered as a potential new target for the treatment of this disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport Systems, Acidic / genetics
  • Amino Acid Transport Systems, Acidic / physiology*
  • Animals
  • Anxiety / metabolism
  • Anxiety / physiopathology*
  • Autoreceptors / physiology
  • Cerebral Cortex / physiopathology
  • Hippocampus / physiopathology
  • Mice
  • Mice, Knockout
  • Presynaptic Terminals / metabolism
  • Raphe Nuclei / physiopathology
  • Receptor, Serotonin, 5-HT1A / physiology
  • Serotonin / physiology*
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Synaptic Transmission
  • Vesicular Monoamine Transport Proteins / metabolism


  • Amino Acid Transport Systems, Acidic
  • Autoreceptors
  • Serotonin Plasma Membrane Transport Proteins
  • Slc18a2 protein, mouse
  • Vesicular Monoamine Transport Proteins
  • vesicular glutamate transporter 3, mouse
  • Receptor, Serotonin, 5-HT1A
  • Serotonin