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The vesicular glutamate transporter VGLUT3 synergizes striatal acetylcholine tone

Abstract

Three subtypes of vesicular transporters accumulate glutamate into synaptic vesicles to promote its vesicular release. One of the subtypes, VGLUT3, is expressed in neurons, including cholinergic striatal interneurons, that are known to release other classical transmitters. Here we showed that disruption of the Slc17a8 gene (also known as Vglut3) caused an unexpected hypocholinergic striatal phenotype. Vglut3−/− mice were more responsive to cocaine and less prone to haloperidol-induced catalepsy than wild-type littermates, and acetylcholine release was decreased in striatum slices lacking VGLUT3. These phenotypes were associated with a colocalization of VGLUT3 and the vesicular acetylcholine transporter (VAChT) in striatal synaptic vesicles and the loss of a synergistic effect of glutamate on vesicular acetylcholine uptake. We propose that this vesicular synergy between two transmitters is the result of the unbalanced bioenergetics of VAChT, which requires anion co-entry for continuing vesicular filling. Our study reveals a previously unknown effect of glutamate on cholinergic synapses with potential functional and pharmacological implications.

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Figure 1: Targeted disruption of the mouse VGLUT3 gene.
Figure 2: Effect of VGLUT3 deletion on locomotor activity.
Figure 3: Vglut3−/− mutants are less prone to haloperidol-induced catalepsy.
Figure 4: The centrally active AChE inhibitor donepezil rescues the hyperlocomotor phenotype of VGLUT3-defective mice.
Figure 5: VGLUT3 deletion reduces striatal ACh release.
Figure 6: VGLUT3 is present on striatal cholinergic vesicles and stimulates vesicular acetylcholine loading.

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Acknowledgements

We thank S. Pérez, E. Etienne and L. Hillard for their excellent technical assistance with release experiments, confocal microscopy and animal care, respectively. This work was supported by grants from INSERM, Fédération pour la Recherche sur le Cerveau and Agence Nationale pour la Recherche. C.G. was supported by a fellowship from Fondation pour la Recherche Médicale and E.M.L. by France Alzheimer.

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Correspondence to Salah El Mestikawy.

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Gras, C., Amilhon, B., Lepicard, È. et al. The vesicular glutamate transporter VGLUT3 synergizes striatal acetylcholine tone. Nat Neurosci 11, 292–300 (2008). https://doi.org/10.1038/nn2052

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