Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 8262-8275 |
| Number of pages | 14 |
| Journal | Journal of Neuroscience |
| Volume | 40 |
| Issue number | 43 |
| DOIs | |
| State | Published - Oct 21 2020 |
Funding
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 L\u00E9vesque 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\u2019s present address: Department of Neurology and Neurosurgery, McGill University, Montreal Neurological Institute, Montr\u00E9al, Qu\u00E9bec H3A 2B4, Canada. Correspondence should be addressed to Louis-Eric Trudeau at [email protected]. https://doi.org/10.1523/JNEUROSCI.0823-20.2020 Copyright \u00A9 2020 the authors 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 L?vesque 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.
Keywords
- Axonal
- Dopamine
- Glutamate
- Parkinson's
- Reinnervation
- Sprouting
ASJC Scopus subject areas
- General Neuroscience