title: Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo.
abstract: Disruption of neurotransmitter vesicle dynamics (transport, capacity, release) has been implicated in a variety of neurodegenerative and neuropsychiatric conditions. Here, we report a novel mouse model of enhanced vesicular function via bacterial artificial chromosome (BAC)-mediated overexpression of the vesicular monoamine transporter 2 (VMAT2; Slc18a2). A twofold increase in vesicular transport enhances the vesicular capacity for dopamine (56%), dopamine vesicle volume (33%), and basal tissue dopamine levels (21%) in the mouse striatum. The elevated vesicular capacity leads to an increase in stimulated dopamine release (84%) and extracellular dopamine levels (44%). VMAT2-overexpressing mice show improved outcomes on anxiety and depressive-like behaviors and increased basal locomotor activity (41%). Finally, these mice exhibit significant protection from neurotoxic insult by the dopaminergic toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), as measured by reduced dopamine terminal damage and substantia nigra pars compacta cell loss. The increased release of dopamine and neuroprotection from MPTP toxicity in the VMAT2-overexpressing mice suggest that interventions aimed at enhancing vesicular capacity may be of therapeutic benefit in Parkinson disease.
authors: Department of Environmental Health, Rollins School of Public Health.
authors: Kelly M
authors: KM
authors: Lohr
authors: Department of Environmental Health, Rollins School of Public Health.
authors: Alison I
authors: AI
authors: Bernstein
authors: Department of Environmental Health, Rollins School of Public Health.
authors: Kristen A
authors: KA
authors: Stout
authors: Department of Environmental Health, Rollins School of Public Health.
authors: Amy R
authors: AR
authors: Dunn
authors: Department of Environmental Health, Rollins School of Public Health.
authors: Carlos R
authors: CR
authors: Lazo
authors: Department of Environmental Health, Rollins School of Public Health.
authors: Shawn P
authors: SP
authors: Alter
authors: Department of Environmental Health, Rollins School of Public Health.
authors: Minzheng
authors: M
authors: Wang
authors: Department of Environmental Health, Rollins School of Public Health.
authors: Yingjie
authors: Y
authors: Li
authors: Department of Pharmacology.
authors: Xueliang
authors: X
authors: Fan
authors: Department of Pharmacology,Department of Neurology.
authors: Ellen J
authors: EJ
authors: Hess
authors: Robert P. Apkarian Integrated Electron Microscopy Core, and.
authors: Hong
authors: H
authors: Yi
authors: Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada M5S 1A8; and.
authors: Laura M
authors: LM
authors: Vecchio
authors: National Institute of Neurological Disorders and Stroke, Bethesda, MD 20824.
authors: David S
authors: DS
authors: Goldstein
authors: Department of Environmental Health, Rollins School of Public Health.
authors: Thomas S
authors: TS
authors: Guillot
authors: Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada M5S 1A8; and.
authors: Ali
authors: A
authors: Salahpour
authors: Department of Environmental Health, Rollins School of Public Health,Department of Pharmacology,Department of Neurology,Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322; gary.miller@emory.edu.
authors: Gary W
authors: GW
authors: Miller
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal; D022202:Chromosomes, Artificial, Bacterial; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine
keywords: SLC18A2; fast-scan cyclic voltammetry; norepinephrine; serotonin