Role for VGLUT2 in selective vulnerability of midbrain dopamine neurons
Thomas Steinkellner, … , Zachary Freyberg, Thomas S. Hnasko
Thomas Steinkellner, … , Zachary Freyberg, Thomas S. Hnasko
Published January 16, 2018
Citation Information: J Clin Invest. 2018;128(2):774-788. https://doi.org/10.1172/JCI95795.
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Research Article Neuroscience

Role for VGLUT2 in selective vulnerability of midbrain dopamine neurons

Abstract

Parkinson’s disease is characterized by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). DA neurons in the ventral tegmental area are more resistant to this degeneration than those in the SNc, though the mechanisms for selective resistance or vulnerability remain poorly understood. A key to elucidating these processes may lie within the subset of DA neurons that corelease glutamate and express the vesicular glutamate transporter VGLUT2. Here, we addressed the potential relationship between VGLUT expression and DA neuronal vulnerability by overexpressing VGLUT in DA neurons of flies and mice. In Drosophila, VGLUT overexpression led to loss of select DA neuron populations. Similarly, expression of VGLUT2 specifically in murine SNc DA neurons led to neuronal loss and Parkinsonian behaviors. Other neuronal cell types showed no such sensitivity, suggesting that DA neurons are distinctively vulnerable to VGLUT2 expression. Additionally, most DA neurons expressed VGLUT2 during development, and coexpression of VGLUT2 with DA markers increased following injury in the adult. Finally, conditional deletion of VGLUT2 made DA neurons more susceptible to Parkinsonian neurotoxins. These data suggest that the balance of VGLUT2 expression is a crucial determinant of DA neuron survival. Ultimately, manipulation of this VGLUT2-dependent process may represent an avenue for therapeutic development.

Authors

Thomas Steinkellner, Vivien Zell, Zachary J. Farino, Mark S. Sonders, Michael Villeneuve, Robin J. Freyberg, Serge Przedborski, Wei Lu, Zachary Freyberg, Thomas S. Hnasko

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Figure 4

Heterologous expression of VGLUT2 in DA neurons induces Parkinsonian behavior.

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Heterologous expression of VGLUT2 in DA neurons induces Parkinsonian beh...
WT VGLUT2 or GFP (control) was unilaterally expressed in the SNc of DATCre mice, and mice were tested in the open field beginning 21 days after surgery. (A) VGLUT2 expression significantly reduced spontaneous locomotor activity [left panel: 2-way ANOVA followed by Sidak’s multiple comparisons; main effect of treatment: F(1,312) = 86, P < 0.0001; right panel: unpaired t test, t = 3.7, df = 26, P = 0.001; GFP n = 12, VGLUT2 n = 17]. (B and C) Heterologous VGLUT2 expression significantly decreased locomotion in response to amphetamine [B; left panel: 2-way ANOVA followed by Sidak’s multiple comparisons; main effect of treatment: F(1,972) = 233, P < 0.0001; right panel: unpaired t test, t = 2.6, df = 27, P = 0.01; GFP n = 13, VGLUT2 n = 16] or cocaine [C; left panel: 2-way ANOVA followed by Sidak’s multiple comparisons; main effect of treatment: F(1,1008) = 132, P < 0.0001; right panel: unpaired t test: t = 2.8, df = 28, P = 0.01; GFP n = 13, VGLUT2 n = 17]. Left panels show time courses in 5-minute bins; right panels are summated over 60 minutes. (D) Unilateral VGLUT2 expression led to ipsiversive rotational behavior [2-way ANOVA followed by Sidak’s multiple comparisons; main effect of treatment: F(1,56) = 25, P < 0.0001; GFP n = 13, VGLUT2 n = 17]. (E and F) Rotations were reversed to contraversive by apomorphine [E; 2-way ANOVA followed by Sidak’s multiple comparisons; main effect of treatment: F(1,56) = 4.5, P = 0.04; GFP n = 13, VGLUT2 n = 17] or l-DOPA/benserazide [F; 2-way ANOVA followed by Sidak’s multiple comparisons; main effect of treatment: F(1,56) = 11, P = 0.002; GFP n = 13, VGLUT2 n = 17]. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.