| Abstract No.: | A-B1047 |
| Country: | Canada |
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| Title: | STIMULATION OF STRIATAL CHOLINERGIC TRANSMISION BY THE VESICULAR GLUTAMATE TRANSPORTER VGLUT3 |
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| Authors/Affiliations: | 6 Salah El Mestikawy*; 4 Christelle Gras; 3 Bénédicte Amilhon; 2 Ève Lepicard; 3 Odile Poirel; 5 Marie-Louise Kemel; 1 Bruno Gasnier; 6 Bruno Giros;
1 CNRS UPR 1929, Institut de Biologie Physico-Chimique; 2 INSERM U513, Université Paris 6; 3 INSERM U513, Université Paris 6; 4 INSERM U667, Collège de France; 5 INSERM U667,Collège de France; 6 McGill University;
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| Content: | Objectives: Before its exocytotic release glutamate is accumulated into synaptic vesicles by proton-driven membrane transporters named VGLUT1-3. VGLUT1 and VGLUT2 are expressed in classical glutamatergic nerve terminals establishing asymmetrical contacts. It was therefore unexpected to discover that VGLUT3, with transport properties similar to those of VGLUT1 and VGLUT2, is expressed in discrete populations of neurons releasing other non-peptide transmitters, including cholinergic interneurons from the dorsal and ventral striatum, serotoninergic neurons of the medial and dorsal raphe nuclei, and subsets of GABAergic neurons in the hippocampus and cerebral cortex. The function of VGLUT3 in these neurons remains largely unknown.
Materials and Methods: To address this question, we focused on striatal cholinergic interneurons. A mice line lacking VGLUT3 was produced a mouse line and analyzed its phenotype at behavioral, pharmacological, biochemical and anatomical levels.
Results: Knock out animals no longer express VGLUT3 mRNA or protein. No major histological changes were observed in the striatum of these animals. Expression levels of cholinergic dopaminergic, GABAergic and glutamatergic neuron markers were not affected by the deletion of VGLUT3. The striatum is involved in the planning and modulation of movement; we thus assessed locomotor activity. Quantification of locomotor activity by actimetry revealed that VGLUT3-/- mice are hyperactive compared to wild type. In addition, mutant mice are more responsive to cocaine and less prone to haloperidol-induced catalepsy than wild-type littermates. Release experiments of [3H]acetylcholine (Ach) and [3H]dopamine (DA) were performed with striatal slices. [3H]ACh release evoked by the glutamatergic agonist NMDA was reduced by ~40% in VGLUT3-deficient slices (Fig. 5a), thus showing a selective secretory defect of cholinergic interneurones. We then performed immunoisolation of VGLUT3-positive striatal vesicles and found VAChT and VGLUT3 are coexpressed in a subset of striatal synaptic vesicles. To further investigate the consequences of this co-expression of VAChT and VGLUT3, neurotransmitter uptake experiments were performed on striatal synaptic vesicles. We found that cholinergic rat striatal synaptic vesicles, thanks to the presence of VGLUT3, are able to store more ACh in the presence of glutamate.
Conclusion: We concluded from these observations that glutamate synergizes acetylcholine filling into VGLUT3-containing vesicles and consequently increases cholinergic transmission in the striatum. This study unravels an unexpected function of glutamate as an enhancer of ACh vesicular uptake and neurotransmission. In addition to its multiple roles in the central nervous system, glutamate is able to modulate another neurotransmission at the vesicular level.
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