UC San Diego

Parkinson Disease (PD) is known as one of the most common neurodegenerative diseases and affects 1%-2% of the population (1). Previous research suggests that PD is caused by the loss of dopaminergic (DA) neurons in substantia nigra pars compacta (SNc) in midbrain areas (6). The ability of DA neurons in some midbrain areas, such as ventral tegmental area (VTA), to endogenously express vesicular glutamate transporter 2 (Vglut2) and co-release glutamate has been proved to increase the dopamine uptake in DA neurons (11). The dynamic regulation of Vglut2 expression in SNc DA neurons has an important influence in the cell survival. Firstly, in mammalian and Drosophila melanogaster PD models and when SNc DA neurons are injured, the endogenous upregulation of vesicular glutamate transporter 2 (Vglut2) is proved to be neuroprotective to the SNc DA neurons (6). However, heterologous expression of Vglut2 in SNc DA neurons causes the loss of these DA neurons. To explore the mechanism governing Vglut2 regulation in SNc DA neurons, we analyzed the co-localization level between Vglut2 messenger RNA (mRNA) and tyrosine hydroxylase (TH) mRNA as a marker for DA neurons with high dosage of amphetamine (AMPH) to acutely deplete dopamine in SNc DA neurons. We hypothesize that dopamine stress caused by high dosage of amphetamine will upregulate Vglut2 expression potentially as a compensatory way to increase dopamine releasing in SNc DA neurons.

Here, our results indicate that the co-localization rate between Vglut2 mRNA and TH mRNA increases after treatment of high dosage amphetamine to DA neurons in the SNc. The increased co-localization rate suggests that dopamine depletion increases the number of SNc DA neurons co-expressing Vglut2. With knowing the potential mechanism governing Vglut2 dynamic regulation in SNc DA neurons, we might have a clearer understanding the role of Vglut2 expression in DA neuron loss in PD and thus provide potential new strategies in PD intervention.