From glutamate co-release to vesicular synergy: vesicular glutamate transporters

• Published in: Nature reviews. Neuroscience Vol. 12; no. 4; pp. 204 - 216
• Main Authors: Trudeau, Louis-Eric, El Mestikawy, Salah, Wallén-Mackenzie, Åsa, Fortin, Guillaume M, Descarries, Laurent
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2011; Nature Publishing Group
• Subjects: 631/378/548/1964; 631/378/548/2590; 87; Acetylcholine; Animal Genetics and Genomics; Animals; Behavioral Sciences; Biochemistry. Physiology. Immunology; Biological and medical sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Brain - cytology; Brain - metabolism; Brain research; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; Fundamental and applied biological sciences. Psychology; GABA; Genotype & phenotype; Glutamate; Glutamic Acid - metabolism; Hypotheses; Invertebrates; MEDICIN; MEDICINE; Mollusca; Nervous system; Neurobiology; Neurons; Neurons - metabolism; Neurosciences; Neurotransmitter Agents - metabolism; Physiological aspects; Physiology. Development; Protons; review-article; Transmitters; Vertebrates: nervous system and sense organs; Vesicular Glutamate Transport Proteins - classification; Vesicular Glutamate Transport Proteins - physiology; France; Canada; Sweden; Quebec Canada; Cholinergic neuron; Phenotype; Functional organization; Glutamatergic neuron; Excitatory aminoacid; Neurotransmitter; Review; Glutamate; Synergism; Release; Gabaergic neuron
• ISSN: 1471-003X; 1471-0048; 1471-0048; 1469-3178
• DOI: 10.1038/nrn2969

Key Points 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. Vesicular glutamate transporters are expressed not only in glutamate neurons but also in monoamine, acetylcholine and, intriguingly, GABA neurons. Trudeau and colleagues discuss the role of these transporters in glutamate co-release and vesicular synergy — a process leading to enhanced packaging of the 'primary' transmitter. 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.