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

Hui Shen, Rosa Anna M. Marino, Ross A. McDevitt, Guo Hua Bi, Kai Chen, Graziella Madeo, Pin Tse Lee, Ying Liang, Lindsay M. De Biase, Tsung Ping Su, Zheng Xiong Xi, Antonello Bonci

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4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)E11532-E11541
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number49
DOIs
Publication statusPublished - Dec 4 2018
Externally publishedYes

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Keywords

  • BDNF
  • Midbrain DA neurons
  • MPTP
  • Parkinson’s disease
  • VgluT2

ASJC Scopus subject areas

  • General

Cite this

Shen, H., Marino, R. A. M., McDevitt, R. A., Bi, G. H., Chen, K., Madeo, G., Lee, P. T., Liang, Y., De Biase, L. M., Su, T. P., Xi, Z. X., & Bonci, A. (2018). Genetic deletion of vesicular glutamate transporter in dopamine neurons increases vulnerability to MPTP-induced neurotoxicity in mice. Proceedings of the National Academy of Sciences of the United States of America, 115(49), E11532-E11541. https://doi.org/10.1073/pnas.1800886115