Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo

• Type of Material: Article
• Authors: Kelly M. Lohr, Emory University; Alison I. Bernstein, Emory University; Kristen A. Stout, Emory University; Amy R. Dunn, Emory University; Carlos R. Lazo, Emory University; Shawn P. Alter, Emory University; Minzheng Wang, Emory University; Yingjie Li, Emory University; Xueliang Fan, Emory University; Ellen Hess, Emory University; Hong Yi, Emory University; Laura M. Vecchio, University of Toronto; David S. Goldstein, National Institute of Neurological Disorders and Stroke; Thomas S. Guillot, Emory University; Ali Salahpour, University of Toronto; Gary Miller, Emory University
• Language: English
• Date: 2014-07-08
• Publisher: NATL ACAD SCIENCES
• Publication Version: Final Published Version
• Copyright Statement: National Academy of Sciences
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1402134111
• Title of Journal or Parent Work: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• Volume: 111
• Issue: 27
• Start Page: 9977
• End Page: 9982
• Grant/Funding Information: This work was supported by National Institutes of Health Grants P01ES016731, P30ES019776, T32ES012870, DA015040, T32GM008605, F31NS084739, P50AG025688, and P50NS071669; Canadian Institutes of Health Research Grant 210296; and the Lewis Dickey Memorial Fund.
• Keywords: Multidisciplinary Sciences; fast-scan cyclic voltammetry; serotonin; QUANTAL SIZE; NEURONS; SLC18A2; BRAIN; MOUSE MODEL; KNOCKOUT MICE; norepinephrine; AMPHETAMINE; Science & Technology; STORAGE; COCAINE; ALPHA-SYNUCLEIN; Science & Technology - Other Topics; EXPRESSION
• Research Categories: Health Sciences, Pharmacology; Biology, Neuroscience

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.