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Proc Natl Acad Sci U S A. 2014 Jul 8;111(27):9977-82. doi: 10.1073/pnas.1402134111. Epub 2014 Jun 16.

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

Author information

1
Department of Environmental Health, Rollins School of Public Health.
2
Department of Pharmacology.
3
Department of Pharmacology,Department of Neurology.
4
Robert P. Apkarian Integrated Electron Microscopy Core, and.
5
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada M5S 1A8; and.
6
National Institute of Neurological Disorders and Stroke, Bethesda, MD 20824.
7
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.

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.

KEYWORDS:

SLC18A2; fast-scan cyclic voltammetry; norepinephrine; serotonin

PMID:
24979780
PMCID:
PMC4103325
DOI:
10.1073/pnas.1402134111
[Indexed for MEDLINE]
Free PMC Article

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