A Third Vesicular Glutamate Transporter Expressed by Cholinergic and Serotoninergic Neurons

Abstract

Two proteins previously known as Na(+)-dependent phosphate transporters have been identified recently as vesicular glutamate transporters (VGLUT1 and VGLUT2). Together, VGLUT1 and VGLUT2 are operating at most central glutamatergic synapses. In this study, we characterized a third vesicular glutamate transporter (VGLUT3), highly homologous to VGLUT1 and VGLUT2. Vesicles isolated from endocrine cells expressing recombinant VGLUT3 accumulated l-glutamate with bioenergetic and pharmacological characteristics similar, but not identical, to those displayed by the type-1 and type-2 isoforms. Interestingly, the distribution of VGLUT3 mRNA was restricted to a small number of neurons scattered in the striatum, hippocampus, cerebral cortex, and raphe nuclei, in contrast to VGLUT1 and VGLUT2 transcripts, which are massively expressed in cortical and deep structures of the brain, respectively. At the ultrastructural level, VGLUT3 immunoreactivity was concentrated over synaptic vesicle clusters present in nerve endings forming asymmetrical as well as symmetrical synapses. Finally, VGLUT3-positive neurons of the striatum and raphe nuclei were shown to coexpress acetylcholine and serotonin transporters, respectively. Our study reveals a novel class of glutamatergic nerve terminals and suggests that cholinergic striatal interneurons and serotoninergic neurons from the brainstem may store and release glutamate.

Vesicular glutamate transporter 3-immunoreactive pericellular baskets ensheath a distinct population of neurons in the lateral septum

“…In the basal forebrain, axonal co-expression of VGLUT3-immunoreactivity was shown for the striatal cholinergic interneurons. In contrast, the VGLUT3-ir fibrous structures in the LS did not co-express acetylcholine, serotonin and, only rarely, GABA (Fremeau et al, 2002;Gras et al, 2002;Herzog et al, 2004).…”

“…In contrast, VGLUT3-mRNA was found in deeper brain areas like hypothalamus, substantia nigra and dorsal raphe (Fremeau et al, 2002;Gras et al, 2002;Herzog et al, 2004;Schäfer et al, 2002). Projection neurons located in these regions innervate the LS and their terminals form perisomatic and peridendritic plexus called pericellular baskets (Jakab and Leranth, 1995).…”

Vesicular glutamate transporter‐1 colocalizes with endogenous opioid peptides in axon terminals of the rat locus coeruleus

“…Three isoforms of VGLUT have so far been established. Two are recognized as definitive markers of glutamatergic neurons and their axon terminals (VGLUT1, VGLUT2) (Bellocchio et al, 1998(Bellocchio et al, , 2000Takamori et al, 2000;Fremeau et al, 2001Fremeau et al, , 2002Herzog et al, 2001;Hisano et al, 2002;Hisano, 2003) and a third is expressed by cholinergic and serotonergic neurons (VGLUT3) (Gras et al, 2002;Schafer et al, 2002). VGLUT1 mRNA expression in distinct regions of rat and human brain has been confirmed by in situ hybridization studies (Ni et al, 1994(Ni et al, , 1996Hisano et al, 2002;Hioki et al, 2003;Hisano, 2003).…”

VGLUT3, un acteur insoupçonné de la transmission cholinergique striatale

“…Trois transporteurs vésiculaires du glutamate (VGLUT1 à -3) ont été découverts au début de ce siècle [1][2][3]. Ces protéines sont à la fois des marqueurs fonctionnels et anatomiques des neurones glutamatergiques.…”

“…En effet, elle est restreinte à des sous-populations neuronales décrites comme non glutamatergiques. On le trouve notamment dans certains interneurones GABAergiques du cortex et de l'hippocampe, dans les neurones sérotoninergiques du raphé et enfin dans les interneurones cholinergiques du striatum, auxquels nous nous sommes plus particulièrement intéressés [3,10]. Cette présence insolite (Figure 1) pose la question d'une possible cotransmission (colibération de deux neurotransmetteurs habituellement non associés).…”