title: Limiting glutamate transmission in a Vglut2-expressing subpopulation of the subthalamic nucleus is sufficient to cause hyperlocomotion.
abstract: The subthalamic nucleus (STN) is a key area of the basal ganglia circuitry regulating movement. We identified a subpopulation of neurons within this structure that coexpresses Vglut2 and Pitx2, and by conditional targeting of this subpopulation we reduced Vglut2 expression levels in the STN by 40%, leaving Pitx2 expression intact. This reduction diminished, yet did not eliminate, glutamatergic transmission in the substantia nigra pars reticulata and entopeduncular nucleus, two major targets of the STN. The knockout mice displayed hyperlocomotion and decreased latency in the initiation of movement while preserving normal gait and balance. Spatial cognition, social function, and level of impulsive choice also remained undisturbed. Furthermore, these mice showed reduced dopamine transporter binding and slower dopamine clearance in vivo, suggesting that Vglut2-expressing cells in the STN regulate dopaminergic transmission. Our results demonstrate that altering the contribution of a limited population within the STN is sufficient to achieve results similar to STN lesions and high-frequency stimulation, but with fewer side effects.
authors.affiliation: Units of Functional Neurobiology andDevelopmental Genetics, Department of Neuroscience, Biomedical Center, Uppsala University, S-751 24 Uppsala, Sweden;
authors.forename: Nadine
authors.initials: N
authors.lastname: Schweizer
authors.affiliation: Units of Functional Neurobiology andDevelopmental Genetics, Department of Neuroscience, Biomedical Center, Uppsala University, S-751 24 Uppsala, Sweden;Brain Institute, Federal University of Rio Grande do Norte, 2155-59056-450 Natal-RN, Brazil;
authors.forename: Stéfano
authors.initials: S
authors.lastname: Pupe
authors.affiliation: Units of Functional Neurobiology andDevelopmental Genetics, Department of Neuroscience, Biomedical Center, Uppsala University, S-751 24 Uppsala, Sweden;
authors.forename: Emma
authors.initials: E
authors.lastname: Arvidsson
authors.affiliation: Units of Functional Neurobiology andDevelopmental Genetics, Department of Neuroscience, Biomedical Center, Uppsala University, S-751 24 Uppsala, Sweden;
authors.forename: Karin
authors.initials: K
authors.lastname: Nordenankar
authors.affiliation: Units of Functional Neurobiology andDevelopmental Genetics, Department of Neuroscience, Biomedical Center, Uppsala University, S-751 24 Uppsala, Sweden;
authors.forename: Casey J A
authors.initials: CJ
authors.lastname: Smith-Anttila
authors.affiliation: Faculty of Pharmacy, Université de Montréal, Montréal, QC, Canada H3C 3J7; and.
authors.forename: Souha
authors.initials: S
authors.lastname: Mahmoudi
authors.affiliation: Units of Functional Neurobiology andDevelopmental Genetics, Department of Neuroscience, Biomedical Center, Uppsala University, S-751 24 Uppsala, Sweden;
authors.forename: Anna
authors.initials: A
authors.lastname: Andrén
authors.affiliation: Oramacell, 75006 Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dumas
authors.affiliation: Units of Functional Neurobiology andDevelopmental Genetics, Department of Neuroscience, Biomedical Center, Uppsala University, S-751 24 Uppsala, Sweden;
authors.forename: Aparna
authors.initials: A
authors.lastname: Rajagopalan
authors.affiliation: Faculty of Pharmacy, Université de Montréal, Montréal, QC, Canada H3C 3J7; and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lévesque
authors.affiliation: Developmental Genetics, Department of Neuroscience, Biomedical Center, Uppsala University, S-751 24 Uppsala, Sweden;Brain Institute, Federal University of Rio Grande do Norte, 2155-59056-450 Natal-RN, Brazil;
authors.forename: Richardson N
authors.initials: RN
authors.lastname: Leão
authors.affiliation: Units of Functional Neurobiology andDevelopmental Genetics, Department of Neuroscience, Biomedical Center, Uppsala University, S-751 24 Uppsala, Sweden; asa.mackenzie@neuro.uu.se.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Wallén-Mackenzie
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D006948:Hyperkinesis / Q000209:etiology / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020531:Subthalamic Nucleus / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism*; D000097577:Homeobox Protein PITX2
chemical_list: D004298:Dopamine; D018698:Glutamic Acid; D018398:Homeodomain Proteins; D014157:Transcription Factors; D050599:Vesicular Glutamate Transport Protein 2; D000097577:Homeobox Protein PITX2; C493477:Slc17a6 protein, mouse
keywords: Parkinson disease; deep brain stimulation; optogenetics; striatum; vesicular transporter