TY - JOUR
T1 - VGluT2 expression in dopamine neurons contributes to postlesional striatal reinnervation
AU - Kouwenhoven, Willemieke M.
AU - Fortin, Guillaume
AU - Penttinen, Anna Maija
AU - Florence, Clélia
AU - Delignat-Lavaud, Benoît
AU - Bourque, Marie Josée
AU - Trimbuch, Thorsten
AU - Luppi, Milagros Pereira
AU - Salvail-Lacoste, Alix
AU - Legault, Pascale
AU - Poulin, Jean François
AU - Rosenmund, Christian
AU - Awatramani, Raj
AU - Trudeau, Louis Éric
N1 - Funding Information:
This work was supported by the Canadian Institutes of Health Research (Grant MOP106556; to L.-E.T.); by pilot project grants from Parkinson Canada (to A.S.-L., P.L., and L.-E.T.); by the Brain Canada and Krembil foundations (to L.-E.T.); and by National Institutes of Health Grants R01-MH-110556, R01-NS-096240, and P50-DA-044121-01A1 (to R.A.). We thank Dr. Alexander Weil for access to the StereoInvestigator stereological analysis workstation, Dr. Daniel Lévesque for access to his laboratory space and cryostat, and Dr. Sebastien Talbot for access to his Nikon Ti2 epifluorescence microscope. We also thank Dominic Thibault for technical assistance with the viral preparations. The authors declare no competing financial interests. J.-F. Poulin’s present address: Department of Neurology and Neurosurgery, McGill University, Montreal Neurological Institute, Montréal, Québec H3A 2B4, Canada. Correspondence should be addressed to Louis-Eric Trudeau at louis-eric.trudeau@umontreal.ca. https://doi.org/10.1523/JNEUROSCI.0823-20.2020 Copyright © 2020 the authors
Publisher Copyright:
Copyright © 2020 the authors
PY - 2020/10/21
Y1 - 2020/10/21
N2 - A subset of adult ventral tegmental area dopamine (DA) neurons expresses vesicular glutamate transporter 2 (VGluT2) and releases glutamate as a second neurotransmitter in the striatum, while only few adult substantia nigra DA neurons have this capacity. Recent work showed that cellular stress created by neurotoxins such as MPTP and 6-hydroxydopamine 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 postlesional plasticity. We first took advantage of an in vitro neurotoxin model of Parkinson's disease and found that this caused an average 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.98% of DA neurons have a VGluT21 lineage. Expression of VGluT2 was detectable in most DA neurons at embryonic day 11.5 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 postlesional brain, we observed that DA neurons in female and male mice in which VGluT2 was conditionally removed established fewer striatal connections 7weeks 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 postlesional plasticity of dopaminergic axons.
AB - A subset of adult ventral tegmental area dopamine (DA) neurons expresses vesicular glutamate transporter 2 (VGluT2) and releases glutamate as a second neurotransmitter in the striatum, while only few adult substantia nigra DA neurons have this capacity. Recent work showed that cellular stress created by neurotoxins such as MPTP and 6-hydroxydopamine 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 postlesional plasticity. We first took advantage of an in vitro neurotoxin model of Parkinson's disease and found that this caused an average 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.98% of DA neurons have a VGluT21 lineage. Expression of VGluT2 was detectable in most DA neurons at embryonic day 11.5 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 postlesional brain, we observed that DA neurons in female and male mice in which VGluT2 was conditionally removed established fewer striatal connections 7weeks 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 postlesional plasticity of dopaminergic axons.
KW - Axonal
KW - Dopamine
KW - Glutamate
KW - Parkinson's
KW - Reinnervation
KW - Sprouting
UR - http://www.scopus.com/inward/record.url?scp=85094220295&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85094220295&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0823-20.2020
DO - 10.1523/JNEUROSCI.0823-20.2020
M3 - Article
C2 - 32928885
AN - SCOPUS:85094220295
SN - 0270-6474
VL - 40
SP - 8262
EP - 8275
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 43
ER -