Vesicular transporters accumulate neurotransmitters in synaptic vesicles before their regulated release. They are key functional markers as they define the 'transmitter phenotype' of a given neuron.
Vesicular glutamate transporters (VGLUTs) are found not only in neurons previously known to use glutamate as their primary transmitter but also in 'non-glutamatergic' neurons, including some that release a monoamine, acetylcholine or GABA.
The role of VGLUTs in these non-glutamatergic neurons is the subject of intense research. Two major roles have thus far been proposed: co-release of glutamate as a co-transmitter and enhanced packaging of the primary transmitter through a mechanism called 'vesicular synergy'.
The co-release of glutamate by serotonin (5-HT), dopamine and acetylcholine neurons was initially demonstrated in vitro, in isolated neuron microcultures. These initial discoveries were recently validated in vivo in the mouse, using optogenetics and patch-clamp electrophysiology.
Vesicular synergy is emerging as an important function of VGLUTs in acetylcholine, serotonin and dopamine neurons. Its molecular mechanisms are still incompletely defined.
The behavioural consequences of glutamate co-release and/or vesicular synergy by dopamine, serotonin, acetylcholine or GABA neurons have only recently begun to be explored.
Recent work in knockout mice suggests: first, that vesicular glutamate transporter 2 (VGLUT2) in dopamine neurons regulates behavioural activation induced by psychostimulant drugs; second, that VGLUT3 in cholinergic interneurons regulates basal and cocaine-stimulated locomotor activity; and third, that VGLUT3 in 5-HT neurons regulates anxiety-related behaviours.
Recent data indicate that 'classical' neurotransmitters can also act as co-transmitters. This notion has been strengthened by the demonstration that three vesicular glutamate transporters (vesicular glutamate transporter 1 (VGLUT1), VGLUT2 and VGLUT3) are present in central monoamine, acetylcholine and GABA neurons, as well as in primarily glutamatergic neurons. Thus, intriguing questions are raised about the morphological and functional organization of neuronal systems endowed with such a dual signalling capacity. In addition to glutamate co-release, vesicular synergy — a process leading to enhanced packaging of the 'primary' transmitter — is increasingly recognized as a major property of the glutamatergic co-phenotype. The behavioural relevance of this co-phenotype is presently the focus of considerable interest.
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Research in the El Mestikawy Laboratory was supported by grants from the Institut National de la Santé et de la Recherche Médicale, Agence Nationale pour la Recherche, Centre National de la Recherche Scientifique, Université Pierre et Marie Curie, Canadian Research chair, Douglas Mental Health University Institute and Canadian Foundation for Innovation. Research in the Mackenzie Laboratory was supported by the Swedish Research Council, the Swedish Brain Foundation, the Åhlén and Wiberg Foundations, the National Board of Health and Welfare and Uppsala University, Sweden. Research in the Descarries Laboratory was supported by grant NRF-3,544 from the Canadian Institutes of Health Research (CIHR). Research in the Trudeau Laboratory was also supported by grants from the CIHR, the National Alliance for Research on Schizophrenia and Depression, Neuroscience Canada and the Natural Sciences and Engineering Research Council of Canada. L.-E.T. and A.W.-M. share a grant from the Swedish Foundation for International Cooperation in Research and Higher Education. The authors thank B. Amilhon for help in the design of Figure. 2, N. Bérubé-Carrière for help in the preparation of Table 1 and B. Gasnier for fruitful discussions.
The authors declare no competing financial interests.
- Asymmetrical synapse
An asymmetrical synapse (or Gray type I synapse) contains predominantly round or spherical small synaptic vesicles and are characterized by a thickened postsynaptic density. Asymmetrical synapses are thought to be excitatory.
- Tyrosine hydroxylase
The enzyme that converts tyrosine to dihydroxyphenylalanine (DOPA). This reaction is the rate-limiting step in the biosynthesis of catecholamines (dopamine, noradrenaline and adrenaline).
A primary culture system that allows single-neuron cultures by growing neurons on microdroplets of growth substrate.
(ChAT). The enzyme that catalyses the synthesis of acetylcholine from acetyl-CoA and choline. One isoform of ChAT has been identified — this is a specific marker of cholinergic neurons.
- Renshaw cell
A GABAergic interneuron found in the ventral horn of the spinal cord. Renshaw cells form and receive excitatory recurrent collaterals from, and send inhibitory synapses on to, spinal motor neurons.
The use of genetically encoded light-activated proteins (for example, ion channels) to control functional parameters (for example, the membrane potential) of targeted neuronal populations.
- Vesicular inhibitory amino acid transporter
(VIAAT; also known as VGAT). A proton-dependent vesicular transporter that accumulates the inhibitory transmitters GABA and glycine into synaptic vesicles.
- Dopamine transporter
A plasma membrane protein from the family of Na+- and Cl−-dependent transporters. It efficiently takes dopamine up from the extracellular space into neurons (affinity 10−7 M) using energy based on the Na+ gradient generated by the Na+/K+ ATPase.
- Vesicular monoamine transporters
(VMATs). Synaptic vesicle proteins that translocate monoamines (dopamine, noradrenaline, 5HT and histamine) from the cytoplasm into vesicles. The driving force is the proton gradient generated by the vacuolar-type proton ATPase (V-ATPase). Two isoforms have been cloned, VMAT1 in the peripheryand VMAT2 in the CNS. VMATs belong to a large family of sugar transporters that also includes the vesicular acetylcholine transporter (VAChT).
- Tryptophan hydroxylase
(TPH). The rate-limiting enzyme for the biosynthesis of serotonin (5-hydroxytryptamine (5-HT)). TPHs convert tryptophan to 5-hydroxytryptophan. Two TPH genes have been identified in mammals: TPH1 is expressed in the periphery and TPH2 in raphe nuclei.
- Autaptic connection
A synaptic contact established by a neuron onto its own dendrites or cell body.
- Non-synaptic axon terminal
An axon terminal (varicosity) that displays no morphologically identifiable synaptic membrane specialization (junctional complex). Also referred to as an asynaptic terminal or free nerve ending.
- Vesicular acetylcholine transporters
(VAChTs). Synaptic vesicle proteins mediating the accumulation of acetylcholine into secretory vesicles. VAChTs use the proton gradient generated by the vacuolar-type proton ATPase (V-ATPase) as the driving force.
- Stimulated emission depletion (STED) microscopy
A high-resolution fluorescence microscopy technique that takes advantage of de-excitation of fluorescent dyes to partly overcome the resolution limit imposed by diffraction.
- Total internal reflection fluorescence (TIRF) microscopy
A high-resolution fluorescence microscopy technique that takes advantage of a laser-induced evanescent wave of fluorescence emission very close to the interface of two media that have different refractive indices.
- Conditioned place preference paradigm
A behavioural test commonly used with rodents, in which drug administration is paired with specific environmental cues. On the test day, the proportion of time spent in the chamber previously associated with the drug provides an estimate of the positive subjective properties of the drug, as well as of its addictive potential.
- Miniature synaptic current
A synaptic current that is due to the simultaneous activation of ionotropic receptors following the release of a quantum of neurotransmitter. A mixed miniature synaptic current is possible if two different types of neurotransmitters are present in a given synaptic vesicle and the corresponding receptors are present postsynaptically.
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El Mestikawy, S., Wallén-Mackenzie, Å., Fortin, G. et al. From glutamate co-release to vesicular synergy: vesicular glutamate transporters. Nat Rev Neurosci 12, 204–216 (2011). https://doi.org/10.1038/nrn2969
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