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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

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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 1

dVGLUT overexpression causes loss of select dopaminergic populations in Drosophila.

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dVGLUT overexpression causes loss of select dopaminergic populations in ...
Drosophila VGLUT (dVGLUT) was expressed specifically in DA neurons via the TH-GAL4 expression driver and termed dVGLUT high expressors (dVGLUT HE). dVGLUT HE brains were compared with control brains expressing dVGLUT at WT levels. Presynaptic DA neurons in both dVGLUT HE and control flies were labeled with TH-GAL4–driven GFP and whole living brains visualized by multiphoton microscopy. (A–C) dVGLUT HE brains demonstrated complete loss of DA innervation to the ellipsoid body (EB). Insets in A and B highlight the EB region. Two-way ANOVA; main effect of genotype: F(1,10) = 1,316, P < 0.0001; time × genotype interaction: F(3,30) = 26.5, P < 0.0001. (D–F) While the overall morphology of the fan-shaped body (FSB) was preserved in dVGLUT HE brains, there were fewer DA cell bodies innervating it [2-way ANOVA; main effect of genotype: F(1,9) = 6.6, P = 0.03], and diminished axon length compared with controls [2-way ANOVA; main effect of genotype: F(1,4) = 277, P < 0.0001]. (G) The number of DA neurons innervating the subesophageal ganglion (SEG) showed no significant changes, but axon length in dVGLUT HE was significantly reduced compared with WT [2-way ANOVA; main effect of genotype: F(1,4) = 35.7, P = 0.004]. Comparable results were obtained from n ≥ 3 independent experiments. Images are projected Z series of coronal sections 3 days after eclosion. Scale bars: 50 μm; insets, 25 μm. *P < 0.05, **P < 0.01, ***P < 0.001 across genotype, within time point by Sidak’s multiple-comparisons post hoc.
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