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Proc Natl Acad Sci U S A. 2018 Dec 4;115(49):E11532-E11541. doi: 10.1073/pnas.1800886115. Epub 2018 Nov 15.

Genetic deletion of vesicular glutamate transporter in dopamine neurons increases vulnerability to MPTP-induced neurotoxicity in mice.

Author information

1
Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224.
2
Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224; antonello.bonci@nih.gov.
3
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
4
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
5
Department of Neuroscience, Georgetown University Medical Center, School of Medicine, Washington, DC 20057.
6
Department of Psychiatry, University of Maryland, School of Medicine, Baltimore, MD 21201.

Abstract

A subset of midbrain dopamine (DA) neurons express vesicular glutamate transporter 2 (VgluT2), which facilitates synaptic vesicle loading of glutamate. Recent studies indicate that such expression can modulate DA-dependent reward behaviors, but little is known about functional consequences of DA neuron VgluT2 expression in neurodegenerative diseases like Parkinson's disease (PD). Here, we report that selective deletion of VgluT2 in DA neurons in conditional VgluT2-KO (VgluT2-cKO) mice abolished glutamate release from DA neurons, reduced their expression of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB), and exacerbated the pathological effects of exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, viral rescue of VgluT2 expression in DA neurons of VglutT2-cKO mice restored BDNF/TrkB expression and attenuated MPTP-induced DA neuron loss and locomotor impairment. Together, these findings indicate that VgluT2 expression in DA neurons is neuroprotective. Genetic or environmental factors causing reduced expression or function of VgluT2 in DA neurons may place some individuals at increased risk for DA neuron degeneration. Therefore, maintaining physiological expression and function of VgluT2 in DA neurons may represent a valid molecular target for the development of preventive therapeutic interventions for PD.

KEYWORDS:

BDNF; MPTP; Parkinson’s disease; VgluT2; midbrain DA neurons

PMID:
30442663
PMCID:
PMC6298109
DOI:
10.1073/pnas.1800886115
[Indexed for MEDLINE]
Free PMC Article

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