| Autor: |
Lohr KM; Department of Environmental Health, Rollins School of Public Health., Bernstein AI; Department of Environmental Health, Rollins School of Public Health., Stout KA; Department of Environmental Health, Rollins School of Public Health., Dunn AR; Department of Environmental Health, Rollins School of Public Health., Lazo CR; Department of Environmental Health, Rollins School of Public Health., Alter SP; Department of Environmental Health, Rollins School of Public Health., Wang M; Department of Environmental Health, Rollins School of Public Health., Li Y; Department of Environmental Health, Rollins School of Public Health., Fan X; Department of Pharmacology., Hess EJ; Department of Pharmacology,Department of Neurology., Yi H; Robert P. Apkarian Integrated Electron Microscopy Core, and., Vecchio LM; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada M5S 1A8; and., Goldstein DS; National Institute of Neurological Disorders and Stroke, Bethesda, MD 20824., Guillot TS; Department of Environmental Health, Rollins School of Public Health., Salahpour A; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada M5S 1A8; and., Miller GW; 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. |
| Abstrakt: |
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. |
