Article abstract
Nature Neuroscience 11, 292 - 300 (2008)
Published online: 17 February 2008 | doi:10.1038/nn2052
The vesicular glutamate transporter VGLUT3 synergizes striatal acetylcholine tone
Christelle Gras1,2,10, Bénédicte Amilhon1,2,10, Ève M Lepicard1,2, Odile Poirel1,2, Jacqueline Vinatier1,2, Marc Herbin3, Sylvie Dumas4, Eleni T Tzavara1,2, Mark R Wade5, George G Nomikos5, Naïma Hanoun6, Françoise Saurini6, Marie-Louise Kemel7, Bruno Gasnier8, Bruno Giros1,2,9 & Salah El Mestikawy1,2,9
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.
- Institut National de la Santé et de la Recherche Médicale (INSERM), U513, Université Pierre et Marie Curie, 9 quai Saint Bernard, 75005 Paris, France.
- UMPC Université Paris 06, Neurobiologie et Psychiatrie, 9 quai Saint Bernard, 75005 Paris, France.
- UMR 7179 USM 301 MNHN-CNRS, CP 55, 75005 Paris, France.
- Helios Biosciences, Faculté de Médecine, 8 rue du général Sarrail, 94010 Créteil CEDEX, France.
- AMGEN, Cambridge Research Center, 1 Kendall Sq, Cambridge, MA 02139, USA.
- UMR 677 INSERM/UPMC, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, Paris CEDEX 13, France.
- INSERM U667, Collège de France, 11 place Marcelin Berthelot, 75231 Paris CEDEX 05, France.
- Institut de Biologie Physico-Chimique, Centre National de la Recherche Scientifique, UPR 1929, Université Paris 7 Denis Diderot, 13 rue Pierre et Marie Curie, 75005 Paris, France.
- Douglas Hospital Research Center, Department of Psychiatry, McGill University, 6875 boulevard Lasalle Verdun, Quebec, Canada.
- These authors contributed equally to this work.
Correspondence to: Salah El Mestikawy1,2,9 e-mail: salah.elmestikawy@snv.jussieu.fr
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