Genetic deletion of vesicular glutamate transporter in dopamine neurons increases vulnerability to MPTP-induced neurotoxicity in mice
Open accessAbstract
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.
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Vglut2+ dopamine neurons in the substantia nigra pars compacta are particularly resistant to degeneration in toxin models of Parkinson's disease, and VGLUT2 may play a neuroprotective role by inducing a BDNF/TRKB dependent signaling cascade.
“In toxin models of PD, Vglut2+ DA neurons in the SNc are particularly resistant to degeneration [58,59], and VGLUT2 itself may play a neuroprotective role by inducing a BDNF/TRKB dependent signaling cascade [59].”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [59]
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Cites
Guide for the Care and Use of Laboratory Animals: Eighth Edition
(2011) · doi:10.17226/12910 · Cited by 16,199 · see citing works
Neurotrophin-regulated signalling pathways
Reichardt, L. F. (2006) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2006.1894 · Cited by 2,195 · see citing works
The substantia nigra of the human brain
Damier, P., Hirsch, É. C., Agid, Y., & Graybiel, A. M. (1999) · Brain · doi:10.1093/brain/122.8.1437 · Cited by 1,772 · see citing works
Non-motor symptoms of Parkinson's disease: dopaminergic pathophysiology and treatment
Chaudhuri, К. R., & Schapira, A. H. V. (2009) · The Lancet Neurology · doi:10.1016/s1474-4422(09)70068-7 · Cited by 1,739 · see citing works
Protocol for the MPTP mouse model of Parkinson's disease
Jackson-Lewis, V. R., & Przedborski, S. (2007) · Nature Protocols · doi:10.1038/nprot.2006.342 · Cited by 1,118 · see citing works
Ventral tegmental area: cellular heterogeneity, connectivity and behaviour
Morales, M., & Margolis, E. B. (2017) · Nature reviews. Neuroscience · doi:10.1038/nrn.2016.165 · Cited by 1,108 · see citing works
VGLUTs define subsets of excitatory neurons and suggest novel roles for glutamate
Fremeau, R. T., Voglmaier, S., Seal, R. P., & Edwards, R. H. (2004) · Trends in Neurosciences · doi:10.1016/j.tins.2003.11.005 · Cited by 745 · see citing works
Reduced BDNF mRNA Expression in the Parkinson's Disease Substantia Nigra
Howells, D. W., Porritt, M. J., Wong, J. Y. F., Batchelor, P. E., Kalnins, R., Hughes, A. J., & Donnan, G. A. (2000) · Experimental Neurology · doi:10.1006/exnr.2000.7483 · Cited by 513 · see citing works
Parkinson’s disease: animal models and dopaminergic cell vulnerability
Blesa, J., & Przedborski, S. (2014) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2014.00155 · Cited by 483 · see citing works
MPTP Mouse Models of Parkinson’s Disease: An Update
Meredith, G. E., & Rademacher, D. J. (2011) · Journal of Parkinson's Disease · doi:10.3233/jpd-2011-11023 · Cited by 471 · see citing works
Local cues establish and maintain region-specific phenotypes of basal ganglia microglia
De Biase, L. M., Schuebel, K. E., Fusfeld, Z. H., Jair, K., Hawes, I. A., Cimbro, R., Zhang, H.-Y., Liu, Q.-R., Shen, H., Xi, Z.-X., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.06.020 · Cited by 432 · see citing works
Self-citationBDNF and Hippocampal Synaptic Plasticity
Leal, G., Bramham, C. R., & Duarte, C. B. (2017) · Vitamins and Hormones · doi:10.1016/bs.vh.2016.10.004 · Cited by 425 · see citing works
Inflammatory Process in Parkinsons Disease: Role for Cytokines
Nagatsu, T., & Sawada, M. (2005) · Current Pharmaceutical Design · doi:10.2174/1381612053381620 · Cited by 412 · see citing works
Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo
Hnasko, T. S., Chuhma, N., Zhang, H., Goh, G. Y., Sulzer, D., Palmiter, R. D., Rayport, S., & Edwards, R. H. (2010) · Neuron · doi:10.1016/j.neuron.2010.02.012 · Cited by 405 · see citing works
Mogi, M., Togari, A., Kondo, T., Mizuno, Y., Komure, O., Kuno, S., Ichinose, H., & Nagatsu, T. (1999) · Neuroscience Letters · doi:10.1016/s0304-3940(99)00463-2 · Cited by 394 · see citing works
Maswood, N., Young, J., Tilmont, E. M., Zhang, Z., Gash, D. M., Gerhardt, G. A., Grondin, R., Roth, G. S., Mattison, J. A., Lane, M. A., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0405831102 · Cited by 383 · see citing works
Palmiter, R. D. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1417.003 · Cited by 375 · see citing works
Mattson, M. P., Pedersen, W. A., Duan, W., Culmsee, C., & Camandola, S. (1999) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1999.tb07824.x · Cited by 343 · see citing works
New medications for drug addiction hiding in glutamatergic neuroplasticity
Kalivas, P. W., & Volkow, N. D. (2011) · Molecular Psychiatry · doi:10.1038/mp.2011.46 · Cited by 342 · see citing works
Zhang, H.-Y., Gao, M., Liu, Q.-R., Bi, G.-H., Li, X., Yang, H.-J., Gardner, E. L., Wu, J., & Xi, Z.-X. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1413210111 · Cited by 334 · see citing works
Self-citationBDNF signaling in the formation, maturation and plasticity of glutamatergic and GABAergic synapses
Gottmann, K., Mittmann, T., & Leßmann, V. (2009) · Experimental Brain Research · doi:10.1007/s00221-009-1994-z · Cited by 297 · see citing works
Clarkson, A. N., Overman, J. J., Zhong, S., Mueller, R., Lynch, G., & Carmichael, S. T. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.5780-10.2011 · Cited by 276 · see citing works
Levivier, M., Przedborski, S., Bencsics, C., & Kang, U. (1995) · The Journal of Neuroscience · doi:10.1523/jneurosci.15-12-07810.1995 · Cited by 274 · see citing works
Dobi, A., Margolis, E. B., Wang, H.-L., Harvey, B. K., & Morales, M. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.3884-09.2010 · Cited by 257 · see citing works
Beal, M. F., Matthews, R. T., Tieleman, A., & Shults, C. W. (1998) · Brain Research · doi:10.1016/s0006-8993(97)01192-x · Cited by 256 · see citing works
Dopaminergic and glutamatergic microdomains in a subset of rodent mesoaccumbens axons
Zhang, S., Qi, J., Li, X., Wang, H.-L., Britt, J. P., Hoffman, A. F., Bonci, A., Lupica, C. R., & Morales, M. (2015) · Nature Neuroscience · doi:10.1038/nn.3945 · Cited by 252 · see citing works
Self-citationKawano, M., Kawasaki, A., Sakata‐Haga, H., Fukui, Y., Kawano, H., Nogami, H., & Hisano, S. (2006) · The Journal of Comparative Neurology · doi:10.1002/cne.21054 · Cited by 230 · see citing works
Glutamate neurons within the midbrain dopamine regions
Morales, M., & Root, D. H. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.05.032 · Cited by 218 · see citing works
Drui, G., Carnicella, S., Carcenac, C., Favier, M., Bertrand, A., Boulet, S., & Savasta, M. (2013) · Molecular Psychiatry · doi:10.1038/mp.2013.3 · Cited by 211 · see citing works
McDevitt, R. A., Tiran-Cappello, A., Shen, H., Balderas, I., Britt, J. P., Marino, R. A. M., Chung, S. L., Richie, C. T., Harvey, B. K., & Bonci, A. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.08.037 · Cited by 203 · see citing works
Self-citationWallén‐Mackenzie, Å., Gezelius, H., Thoby‐Brisson, M., Nygård, A., Enjin, A., Fujiyama, F., Fortin, G., & Kullander, K. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.3855-06.2006 · Cited by 198 · see citing works
Bo, G. D., St-Gelais, F., Danik, M., Williams, S., Cotton, M., & Trudeau, L. (2004) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.02277.x · Cited by 159 · see citing works
Activity-Dependent Dendritic Release of BDNF and Biological Consequences
Kuczewski, N., Porcher, C., Leßmann, V., Medina, I., & Gaïarsa, J. (2009) · Molecular Neurobiology · doi:10.1007/s12035-009-8050-7 · Cited by 158 · see citing works
Glutamatergic and dopaminergic neurons in the mouse ventral tegmental area
Yamaguchi, T., Qi, J., Wang, H., Zhang, S. S., & Morales, M. (2015) · European Journal of Neuroscience · doi:10.1111/ejn.12818 · Cited by 139 · see citing works
The multilingual nature of dopamine neurons
Trudeau, L., Hnasko, T. S., Wallén‐Mackenzie, Å., Morales, M., Rayport, S., & Sulzer, D. L. (2014) · Progress in brain research · doi:10.1016/b978-0-444-63425-2.00006-4 · Cited by 138 · see citing works
Porritt, M. J., Batchelor, P. E., & Howells, D. W. (2005) · Experimental Neurology · doi:10.1016/j.expneurol.2004.11.030 · Cited by 135 · see citing works
Altered expression of vesicular glutamate transporters VGLUT1 and VGLUT2 in Parkinson disease
Kashani, A., Betancur, C., Bruno Giros, A., Hirsch, É. C., & Mestikawy, S. E. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.02.010 · Cited by 132 · see citing works
Zörner, B., Filli, L., Starkey, M. L., Gonzenbach, R. R., Kasper, H., Röthlisberger, M., Bolliger, M., & Schwab, M. E. (2010) · Nature Methods · doi:10.1038/nmeth.1484 · Cited by 128 · see citing works
VGLUT2 in dopamine neurons is required for psychostimulant-induced behavioral activation
Birgner, C., Nordenankar, K., Lundblad, M., Méndez, J. A. T., Smith, C., Grevès, M. L., Galter, D., Olson, L., Fredriksson, A., Trudeau, L., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0910986107 · Cited by 119 · see citing works
Rewarding Effects of Optical Stimulation of Ventral Tegmental Area Glutamatergic Neurons
Wang, H., Qi, J., Zhang, S. S., Wang, H., & Morales, M. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.3428-15.2015 · Cited by 119 · see citing works
Méndez, J. A. T., Bourque, M.-J., Bo, G. D., Bourdeau, M. L., Danik, M., Williams, S., Lacaille, J., & Trudeau, L. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.1331-08.2008 · Cited by 108 · see citing works
Kuczewski, N., Porcher, C., & Gaïarsa, J. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07378.x · Cited by 98 · see citing works
The dual dopamine‐glutamate phenotype of growing mesencephalic neurons regresses in mature rat brain
Bérubé‐Carrière, N., Riad, M., Bo, G. D., Lévesque, D., Trudeau, L., & Descarries, L. (2009) · The Journal of Comparative Neurology · doi:10.1002/cne.22194 · Cited by 98 · see citing works
Glutamate neurons are intermixed with midbrain dopamine neurons in nonhuman primates and humans
Root, D. H., Wang, H., Liu, B., Barker, D. J., Mód, L., Szocsics, P., Silva, A. C., Maglóczky, Z., & Morales, M. (2016) · Scientific Reports · doi:10.1038/srep30615 · Cited by 98 · see citing works
Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT
Aguilar, J. I., Dunn, M., Mingote, S., Karam, C. S., Farino, Z. J., Sonders, M. S., Choi, S. J., Grygoruk, A., Zhang, Y., Cela, C., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.07.038 · Cited by 91 · see citing works
Alsiö, J., Nordenankar, K., Arvidsson, E., Birgner, C., Mahmoudi, S., Halbout, B., Smith, C., Fortin, G. M., Olson, L., Descarries, L., et al. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.2397-11.2011 · Cited by 88 · see citing works
Genetics of Parkinson's Disease
Koros, C., Simitsi, A., & Stefanis, L. (2017) · International review of neurobiology · doi:10.1016/bs.irn.2017.01.009 · Cited by 84 · see citing works
Chuhma, N., Choi, W., Mingote, S., & Rayport, S. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.08.057 · Cited by 83 · see citing works
Activity-dependent BDNF release via endocytic pathways is regulated by synaptotagmin-6 and complexin
Wong, Y., Lee, C.-M. J., 谢文俊, Cui, B., & Poo, M.-M. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1511830112 · Cited by 82 · see citing works
Glutamate Corelease Promotes Growth and Survival of Midbrain Dopamine Neurons
Fortin, G. M., Bourque, M.-J., Méndez, J. A. T., Leo, D., Nordenankar, K., Birgner, C., Arvidsson, E., Rymar, V. V., Bérubé‐Carrière, N., Claveau, A.-M., et al. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.1939-12.2012 · Cited by 77 · see citing works
Increased vulnerability to cocaine in mice lacking dopamine D 3 receptors
Song, R., Zhang, H., Li, X., Bi, G., Gardner, E. L., & Xi, Z. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1205297109 · Cited by 76 · see citing works
Self-citationAdrover, M. F., Shin, J. H., & Alvarez, V. A. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.4958-13.2014 · Cited by 75 · see citing works
Wang, H., & Morales, M. (2008) · The Journal of Comparative Neurology · doi:10.1002/cne.21751 · Cited by 70 · see citing works
Interaction of human and mouse Aβ peptides
Fung, J., Frost, D., Chakrabartty, A., & McLaurin, J. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02828.x · Cited by 59 · see citing works
The LRRK2–macroautophagy axis and its relevance to Parkinson's disease
Manzoni, C. (2017) · Biochemical Society Transactions · doi:10.1042/bst20160265 · Cited by 57 · see citing works
Neurotrophins in the ventral tegmental area: Role in social stress, mood disorders and drug abuse
Nikulina, E. M., Johnston, C. E., Wang, J., & Hammer, R. P. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.05.028 · Cited by 47 · see citing works
Abbott, S. B. G., Holloway, B. B., Viar, K. E., & Guyenet, P. G. (2013) · European Journal of Neuroscience · doi:10.1111/ejn.12421 · Cited by 42 · see citing works
Parkinson-Linked Genes and Toxins That Affect Neuronal Cell Death Through the Bcl-2 Family
Ethell, D. W., & Fei, Q. (2008) · Antioxidants and Redox Signaling · doi:10.1089/ars.2008.2228 · Cited by 41 · see citing works
Wang, D. V., Viereckel, T., Zell, V., Konradsson‐Geuken, Å., Broker, C. J., Talishinsky, A., Yoo, J. H., Galinato, M. H., Arvidsson, E., Kesner, A. J., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.02.062 · Cited by 40 · see citing works
Sgambato, V., & Tremblay, L. (2017) · Journal of Neural Transmission · doi:10.1007/s00702-017-1693-z · Cited by 33 · see citing works
Hurt, C. S., Alkufri, F., Brown, R. G., Burn, D. J., Hindle, J. V., Landau, S., Wilson, K., Samuel, M., & on behalf of the PROMS-PD study group (see acknowledgements) (2014) · Journal of Parkinson s Disease · doi:10.3233/jpd-130314 · Cited by 19 · see citing works
Early-Onset Parkinsonism: Case Report and Review of the Literature
Al-Rumayyan, A. R., Klein, C., & Alfadhel, M. (2015) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2015.06.005 · Cited by 16 · see citing works
Chung, E. K. Y., Chen, L. W., Chan, Y., et al. (2006) · Neurosignals · doi:10.1159/000101704 · Cited by 16 · see citing works
Jabre, M., Nohra, G., Damier, P., et al. (2008) · Stereotactic and Functional Neurosurgery · doi:10.1159/000126941 · Cited by 5 · see citing works
Moderne medikamentöse Therapie des idiopathischen Parkinson-Syndroms
Gasser, T. (1999) · Der Internist · doi:10.1007/s001080050460 · Cited by 1 · see citing works
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Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches
Poulin, J.-F., Gaertner, Z., Moreno-Ramos, O. A., & Awatramani, R. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.01.004 · Cited by 238 · see citing works
- Authors
- 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.
- Affiliations
- National Institute on Drug Abuse (US)
- Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224;
- University of Maryland, Baltimore (US)
- Corresponding author
- Bonci, Antonello
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-11-15
- Volume
- 115
- Issue
- 49
- Pages
- E11532-E11541
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6298109
- OpenAlex
- W2901000494
- Cited by
- 58
- References
- 65
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 8 · 2023: 5 · 2022: 7 · 2021: 8 · 2020: 9 · 2019: 2
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-01-27)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- vesicular glutamate transporter 2, VGLUT2, dopaminergic neurons, MPTP-induced neurotoxicity, Parkinson's disease, brain-derived neurotrophic factor, TrkB, glutamate release, neuroprotection, conditional knockout mice, virus rescue, locomotor impairment, dopaminergic neuron loss
- MeSH terms
- Animals, Gene Expression Regulation, Male, Membrane Glycoproteins, Motor Activity, Mutation, Protein-Tyrosine Kinases, Glutamic Acid, Brain-Derived Neurotrophic Factor, MPTP Poisoning, Receptor, trkB, Vesicular Glutamate Transport Protein 2, Mice, Electrophysiological Phenomena, Dopaminergic Neurons
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