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Salah El Mestikawy"VGLUT3, a presynaptic modulator of modulatory transmission".

Abstract :

Glutamate mediates fast excitatory transmission in the mammalian central nervous system (CNS). Before its exocytotic release, glutamate is loaded into synaptic vesicles by three proton-dependent carriers named VGLUT1-3. These proteins are key elements of excitatory transmission and they define the “glutamatergic phenotype”. VGLUT1 is present in glutamatergic cortical neurons (cerebral, cerebellar and hippocampal cortices) as well as in the thalamus. Subcortical neurons forming a continuum from the diencephalon to the spinal cord preferentially use VGLUT2. VGLUT1 and VGLUT2 display complementary distributions and are present in all canonical glutamatergic terminals. In contrast, VGLUT3 has a discrete expression within 1) cholinergic interneurons of the striatum and nucleus accumbens, 2) a subpopulation of GABAergic basket cells in the hippocampus and the cerebral cortex and 3) the entire population of 5-HT neurons in the raphe nuclei. The role of this unconventional transporter remains mysterious. As demonstrated in the auditory system, VGLUT3 is involved in fast excitatory transmission like the two other subtypes of vesicular glutamate. Thus, VGLUT3 clearly fulfils the function of an actual vesicular glutamatergic transporter, with its expression conferring to neurons the ability to release glutamate. In addition, using a mouse line that no longer expresses VGLUT3 (VGLUT3-KO), we have recently demonstrated that VGLUT3 acts as a positive modulator of striatal cholinergic neurotransmission at the presynaptic level. Because of the presence of VGLUT3, both accumulation of acetylcholine and cholinergic transmission are increased in the striatum relatively to other cholinergic pathways. This new presynaptic regulatory mechanism (that was termed “Vesicular Synergy”) potently and dynamically regulates cholinergic striatal transmission. In summary, VGLUT3 fulfills at least two roles in heterologous neurons: i) modulation of local neurotransmission at the vesicular level through the “primary” transmitter and ii) fast excitatory transmission through the release of glutamate.

Selected publications

RUEL J., EMERY S., BERSOT T., AMILHON B., VAN RYBROEK J. M., REBILLARD G., LENOIR M., EYBALIN M., DELPRAT B., SIVAKUMARAN T. A., GIROS B., EL MESTIKAWY S., SMITH R. J. H., LESPERANCE M. M. AND PUEL J.L. Impairment of vesicular glutamate transporter-3 (VGLUT3) underlies nonsyndromic deafness DFNA25 and selective inner hair cell dysfunction in null mice. American Journal of Human Genetic, 83:278-292 (2008).
GRAS C., AMILHON B., LEPICARD E., KEMEL M.L., HERBIN M., DUMAS S., VINATIER J., TZAVARA E., NOMIKOS G., POIREL O., GASNIER B., GIROS B. AND EL MESTIKAWY S. The vesicular glutamate transporter VGLUT3 synergizes striatal acetylcholine tone. Nature Neurosci 11: 292-300 (2008).

KASHANI A., LEPICARD E., POIREL O., VIDEAU C., DAVID J.P., FALLET-BIANCO C., SIMON A., DELACOURTE A., GIROS B., EPELBAUM J., BETANCUR C., EL MESTIKAWY S. Loss of VGLUT1 and VGLUT2 in the prefrontal cortex is correlated with cognitive decline in Alzheimer disease. Neurobiology of Aging, 29:1619-30. (2008).