Epub – Journal of Neuroscience
VGLUT2 is a determinant of dopamine neuron resilience in a rotenone model of dopamine neurodegeneration

April 23, 2021

Buck SA, De Miranda BR, Logan RW, Fish KN, Greenamyre JT, Freyberg Z

Parkinson’s disease (PD) is characterized by progressive dopamine (DA) neuron loss in the substantia nigra pars compacta (SNc). In contrast, DA neurons in the ventral tegmental area (VTA) are relatively protected from neurodegeneration, but the underlying mechanisms for this resilience remain poorly understood. Recent work suggests that expression of the vesicular glutamate transporter 2 (VGLUT2) selectively impacts midbrain DA neuron vulnerability. We investigated whether altered DA neuron VGLUT2 expression determines neuronal resilience in rats exposed to rotenone, a mitochondrial complex I inhibitor and toxicant model of PD. We discovered that VTA/SNc DA neurons that expressed VGLUT2 are more resilient to rotenone-induced DA neurodegeneration. Surprisingly, the density of neurons with detectable VGLUT2 expression in the VTA and SNc increases in response to rotenone. Furthermore, dopaminergic terminals within the nucleus accumbens, where the majority of VGLUT2-expressing DA neurons project, exhibit greater resilience compared to DA terminals in the caudate/putamen. More broadly, VGLUT2-expressing terminals are protected throughout the striatum from rotenone-induced degeneration. Together, our data demonstrate that a distinct subpopulation of VGLUT2-expressing DA neurons are relatively protected from rotenone neurotoxicity. Rotenone-induced upregulation of the glutamatergic machinery in VTA and SNc neurons and their projections may be part of a broader neuroprotective mechanism. These findings offer a putative new target for neuronal resilience that can be manipulated to prevent toxicant-induced DA neurodegeneration in PD.

Buck SA, De Miranda BR, Logan RW, Fish KN, Greenamyre JT, Freyberg Z. VGLUT2 Is A Determinant Of Dopamine Neuron Resilience In A Rotenone Model Of Dopamine Neurodegeneration. J Neurosci. 2021 Apr 23;JN-RM-2770-20. doi: 10.1523/JNEUROSCI.2770-20.2021. [Epub ahead of print] PubMed PMID: 33893220


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