title: Loss of VGLUT3 Produces Circadian-Dependent Hyperdopaminergia and Ameliorates Motor Dysfunction and l-Dopa-Mediated Dyskinesias in a Model of Parkinson's Disease.
abstract: The striatum is essential for many aspects of mammalian behavior, including motivation and movement, and is dysfunctional in motor disorders such as Parkinson's disease. The vesicular glutamate transporter 3 (VGLUT3) is expressed by striatal cholinergic interneurons (CINs) and is thus well positioned to regulate dopamine (DA) signaling and locomotor activity, a canonical measure of basal ganglia output. We now report that VGLUT3 knock-out (KO) mice show circadian-dependent hyperlocomotor activity that is restricted to the waking cycle and is due to an increase in striatal DA synthesis, packaging, and release. Using a conditional VGLUT3 KO mouse, we show that deletion of the transporter from CINs, surprisingly, does not alter evoked DA release in the dorsal striatum or baseline locomotor activity. The mice do, however, display changes in rearing behavior and sensorimotor gating. Elevation of DA release in the global KO raised the possibility that motor deficits in a Parkinson's disease model would be reduced. Remarkably, after a partial 6-hydroxydopamine (6-OHDA)-mediated DA depletion (∼70% in dorsal striatum), KO mice, in contrast to WT mice, showed normal motor behavior across the entire circadian cycle. l-3,4-dihydroxyphenylalanine-mediated dyskinesias were also significantly attenuated. These findings thus point to new mechanisms to regulate basal ganglia function and potentially treat Parkinson's disease and related disorders.
  
  
  CONCLUSIONS
  Dopaminergic signaling is critical for both motor and cognitive functions in the mammalian nervous system. Impairments, such as those found in Parkinson's disease patients, can lead to severe motor deficits. Vesicular glutamate transporter 3 (VGLUT3) loads glutamate into secretory vesicles for neurotransmission and is expressed by discrete neuron populations throughout the nervous system. Here, we report that the absence of VGLUT3 in mice leads to an upregulation of the midbrain dopamine system. Remarkably, in a Parkinson's disease model, the mice show normal motor behavior. They also show fewer abnormal motor behaviors (dyskinesias) in response to l-3,4-dihydroxyphenylalanine, the principal treatment for Parkinson's disease. The work thus suggests new avenues for the development of novel treatment strategies for Parkinson's disease and potentially other basal-ganglia-related disorders.
authors.affiliation: Department of Neurobiology and.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Divito
authors.affiliation: Michigan State University, College of Human Medicine, Department of Translational Science and Molecular Medicine and The Udall Center of Excellence in Parkinson's Disease Research, Grand Rapids, Michigan 49503.
authors.forename: Kathy
authors.initials: K
authors.lastname: Steece-Collier
authors.affiliation: Department of Neurobiology and.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Case
authors.affiliation: Department of Neurobiology and.
authors.forename: Sean-Paul G
authors.initials: SP
authors.lastname: Williams
authors.affiliation: Michigan State University, College of Human Medicine, Department of Translational Science and Molecular Medicine and The Udall Center of Excellence in Parkinson's Disease Research, Grand Rapids, Michigan 49503.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Stancati
authors.affiliation: Department of Neuroscience, Jefferson College of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Lianteng
authors.initials: L
authors.lastname: Zhi
authors.affiliation: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Rubio
authors.affiliation: Michigan State University, College of Human Medicine, Department of Translational Science and Molecular Medicine and The Udall Center of Excellence in Parkinson's Disease Research, Grand Rapids, Michigan 49503.
authors.forename: Caryl E
authors.identifier: http://orcid.org/0000-0003-2571-6753
authors.initials: CE
authors.lastname: Sortwell
authors.affiliation: Michigan State University, College of Human Medicine, Department of Translational Science and Molecular Medicine and The Udall Center of Excellence in Parkinson's Disease Research, Grand Rapids, Michigan 49503.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Collier
authors.affiliation: Departments of Neurology, Psychiatry, and Pharmacology, Columbia University, New York, New York 10032, and.
authors.forename: David
authors.initials: D
authors.lastname: Sulzer
authors.affiliation: Departments of Neurology and Physiology, University of California, San Francisco School of Medicine, San Francisco, California 94143.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Edwards
authors.affiliation: Department of Neuroscience, Jefferson College of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Neurobiology and Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, rpseal@pitt.edu.
authors.forename: Rebecca P
authors.initials: RP
authors.lastname: Seal
mesh_terms: D026922:Amino Acid Transport Systems, Acidic / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D002940:Circadian Rhythm / Q000502:physiology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000096:biosynthesis*; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism* / Q000517:prevention & control; D005260:Female; D007980:Levodopa / Q000633:toxicity; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019957:Motor Skills Disorders / Q000378:metabolism* / Q000517:prevention & control; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control
chemical_list: D026922:Amino Acid Transport Systems, Acidic; D004298:Dopamine; D007980:Levodopa; C504941:Slc17a8 protein, mouse
keywords: Parkinson's; VGLUT3; acetylcholine; basal ganglia; dopamine; glutamate