title: Role of the atypical vesicular glutamate transporter VGLUT3 in l-DOPA-induced dyskinesia.
abstract: Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons. The gold standard therapy relies on dopamine (DA) replacement by the administration of levodopa (l-DOPA). However, with time l-DOPA treatment induces severe motor side effects characterized by abnormal and involuntary movements, or dyskinesia. Although earlier studies point to a role of striatal cholinergic interneurons, also known as striatal tonically active neurons (TANs), in l-DOPA-induced dyskinesia (LID), the underlying mechanisms remain to be fully characterized. Here, we find that DA depletion is accompanied by increased expression of choline acetyltransferase (ChAT), the vesicular acetylcholine transporter (VAChT) as well as the atypical vesicular glutamate transporter type 3 (VGLUT3). TANs number and soma size are not changed. In dyskinetic mice, the VAChT levels remain high whereas the expression of VGLUT3 decreases. LID is attenuated in VGLUT3-deficient mice but not in mice bearing selective inactivation of VAChT in TANs. Finally, the absence of VGLUT3 is accompanied by a reduction of l-DOPA-induced phosphorylation of ERK1/2, ribosomal subunit (rpS6) and GluA1. Our results reveal that VGLUT3 plays an important role in the development of LID and should be considered as a potential and promising therapeutic target for prevention of LID.
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier F-34094, France; INSERM, U1191, Montpellier F-34094, France; Université de Montpellier, UMR-5203, Montpellier F-34094, France. Electronic address: peppe.ganga@gmail.com.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gangarossa
authors.affiliation: Molecular Medicine, Robarts Research Institute, Departments of Physiology and Pharmacology, Anatomy & Cell Biology, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Monica
authors.initials: M
authors.lastname: Guzman
authors.affiliation: Molecular Medicine, Robarts Research Institute, Departments of Physiology and Pharmacology, Anatomy & Cell Biology, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Vania F
authors.initials: VF
authors.lastname: Prado
authors.affiliation: Molecular Medicine, Robarts Research Institute, Departments of Physiology and Pharmacology, Anatomy & Cell Biology, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Marco A M
authors.initials: MA
authors.lastname: Prado
authors.affiliation: INSERM, UMR-S 1130, F-75005 Paris, France; CNRS, UMR 8246, F-75005 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Institut de Biologie Paris-Seine (IBPS), UM119 Neuroscience Paris Seine, F-75005 Paris, France.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Daumas
authors.affiliation: INSERM, UMR-S 1130, F-75005 Paris, France; CNRS, UMR 8246, F-75005 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06, Institut de Biologie Paris-Seine (IBPS), UM119 Neuroscience Paris Seine, F-75005 Paris, France; Douglas Hospital Research Center, Department of Psychiatry, McGill University, 6875 Boulevard Lasalle Verdun, Quebec, Canada. Electronic address: salah.el_mestikawy@upmc.fr.
authors.forename: Salah
authors.initials: S
authors.lastname: El Mestikawy
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier F-34094, France; INSERM, U1191, Montpellier F-34094, France; Université de Montpellier, UMR-5203, Montpellier F-34094, France. Electronic address: emmanuel.valjent@igf.cnrs.fr.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Valjent
mesh_terms: D026922:Amino Acid Transport Systems, Acidic / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity*; D002452:Cell Count; D048429:Cell Size; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism* / Q000473:pathology; D007980:Levodopa / Q000633:toxicity*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D018091:Receptors, AMPA / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism
chemical_list: D026922:Amino Acid Transport Systems, Acidic; D000978:Antiparkinson Agents; D002795:Choline O-Acetyltransferase; D007980:Levodopa; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016627:Oxidopamine; D018091:Receptors, AMPA; D038601:Ribosomal Protein S6; D050494:Vesicular Acetylcholine Transport Proteins; C493460:Slc18a3 protein, mouse; C448579:ribosomal protein S6, mouse; C504941:Slc17a8 protein, mouse; C535148:Mapk1 protein, mouse
keywords: Acetylcholine; Cell signaling; Cholinergic interneurons (TANs); Dyskinesia; Glutamate; Striatum; Vesicular acetylcholine transporter (VAChT); Vesicular glutamate transporter type 3 (VGLUT3); l-DOPA