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VGLUT2 EXPRESSION IN DOPAMINE NEURONS CONTRIBUTES TO POST-LESIONAL STRIATAL REINNERVATION.

Authors
  • Kouwenhoven, Willemieke M1
  • Fortin, Guillaume1
  • Penttinen, Anna-Maija1
  • Florence, Clélia1
  • Delignat-Lavaud, Benoît1
  • Bourque, Marie-Josée1
  • Trimbuch, Thorsten2
  • Luppi, Milagros Pereira3
  • Salvail-Lacoste, Alix4
  • Legault, Pascale4
  • Poulin, Jean-François3
  • Rosenmund, Christian2
  • Awatramani, Raj3
  • Trudeau, Louis-Éric5
  • 1 Department of Pharmacology and Physiology, Department of Neurosciences, Groupe de Recherche sur le Système Nerveux Central, Faculty of Medicine, Université de Montréal, Montréal, Québec, H3C 3J7.
  • 2 Institut für Neurophysiologie, Charite Universitaetsmedizin, 10117 Berlin, Germany. , (Germany)
  • 3 Department of Neurology and the Center for Genetic Medicine, Northwestern University, Chicago, IL 60611, USA.
  • 4 Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montréal, Québec, H3C 3J7.
  • 5 Department of Pharmacology and Physiology, Department of Neurosciences, Groupe de Recherche sur le Système Nerveux Central, Faculty of Medicine, Université de Montréal, Montréal, Québec, H3C 3J7 [email protected]
Type
Published Article
Journal
Journal of Neuroscience
Publisher
Society for Neuroscience
Publication Date
Sep 14, 2020
Identifiers
DOI: 10.1523/JNEUROSCI.0823-20.2020
PMID: 32928885
Source
Medline
Language
English
License
Unknown

Abstract

A subset of adult ventral tegmental area (VTA) dopamine (DA) neurons expresses Vglut2, a vesicular glutamate transporter, and releases glutamate as a second neurotransmitter in the striatum, while only few adult substantia nigra (SN) DA neurons have this capacity. Recent work showed that cellular stress created by neurotoxins such as MPTP and 6-hydroxydopamine (6-OHDA) can upregulate Vglut2 in surviving DA neurons, suggesting the possibility of a role in cell survival, although a high level of overexpression could be toxic to DA neurons. Here we examined the level of Vglut2 upregulation in response to neurotoxins and its impact on post-lesional plasticity. We first took advantage of an in vitro neurotoxin model of Parkinson's disease (PD) and found that this caused an average of 2.5-fold enhancement of Vglut2 mRNA in DA neurons. This could represent a reactivation of a developmental phenotype because using an intersectional genetic lineage-mapping approach, we find that more than 98% of DA neurons have a Vglut2-positive lineage. Expression of Vglut2 was detectable in most DA neurons at E11.5 and was localized in developing axons. Finally, compatible with the possibility that enhanced Vglut2 expression in DA neurons promotes axonal outgrowth and reinnervation in the post-lesional brain, we observed that DA neurons in female and male mice in which Vglut2 is conditionally removed, established fewer striatal connections 7 weeks after a neurotoxin lesion. Thus, we propose here that the developmental expression of Vglut2 in DA neurons can be reactivated at postnatal stages, contributing to post-lesional plasticity of dopaminergic axons.SIGNIFICANCE STATEMENTA small subset of dopamine neurons in the adult, healthy brain expresses Vglut2, a vesicular glutamate transporter, and thus releases glutamate as a second neurotransmitter in the striatum. This neurochemical phenotype appears to be plastic as exposure to neurotoxins such as 6-OHDA or MPTP, that model certain aspects of Parkinson's Disease pathophysiology, boosts Vglut2 expression in surviving dopamine neurons. Here we show that this enhanced Vglut2 expression in dopamine neurons drives axonal outgrowth and contributes to dopamine neuron axonal plasticity in the post-lesional brain. A better understanding of the neurochemical changes that occur during the progression of Parkinson's disease pathology will aid the development of novel therapeutic strategies for this disease. Copyright © 2020 the authors.

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