VGLUT3 (Vesicular Glutamate Transporter Type 3) Contribution to the Regulation of Serotonergic Transmission and Anxiety

Abstract

Three different subtypes of Hϩ -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.

Gata2 and Gata3 regulate the differentiation of serotonergic and glutamatergic neuron subtypes of the dorsal raphe

“…We show that in the dorsal raphe, most of the medial serotonergic neurons are Vglut3 + and some of these also express Sert (see below), whereas the lateral neurons do not express Vglut3 but are Sert + . This is in contrast to earlier studies, in which Vglut3 and Sert expression was reported to largely colocalise (Gras et al, 2002), although a later study showed that Vglut3 and Sert are detected in distinct nerve terminals in the forebrain (Amilhon et al, 2010 neurons, Gata3 appears to be important for the full serotonergic identity of the Vglut3 + neurons (see below). Thus, distinct serotonergic precursor populations diverge soon after cell cycle exit and show differences in their requirements for terminal selector TFs (Fig.…”

Role for VGLUT2 in selective vulnerability of midbrain dopamine neurons

“…We have previously observed that the vesicular coentry of glutamate through VGLUT can increase the driving force for VMAT2-mediated exchange in both mice and flies (6,54). This mechanism can increase the quantal content of DA and other cationic transmitters (6,(55)(56)(57)(58), but could also help sequester toxic VMAT2 substrates, such as 6-OHDA or 1-methyl-4-phenylpyridinium (MPP + ), away from sensitive cellular compartments or processes. Thus, increased resistance of VGLUT2-expressing DA neurons to neurotoxins is likely to explain at least some of the effects we observe following DA neuron injury with striatal 6-OHDA or systemic MPTP.…”

Vesicular and Plasma Membrane Transporters for Neurotransmitters

“…VGLUT1 is expressed by glutamatergic neurons in the hippocampus and cortex, VGLUT2 in thalamus and brainstem and VGLUT3 in scattered neurons often not associated with the release of glutamate. For example, VGLUT3 is expressed by a subset of GABAergic interneurons as well as cholinergic interneurons of the striatum and serotonergic raphe neurons (Fremeau et al 2002;Gras et al 2002Gras et al , 2008Amilhon et al 2010). In these cells, glutamate transport by VGLUT3 (and by VGLUT2 in DA neurons) both promotes vesicle filling with the other transmitter, and its release activates postsynaptic receptors, as discussed above.…”