Selective deletion of Vglut2 in dopamine neurons increases vulnerability of midbrain dopamine neurons to MPTP

National Institute On Drug Abuse

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Abstract

We found that: 1) under basal conditions (i.e., before MPTP/6-OHDA injection), there is no significant change in midbrain TH-immunostaining, DA cell counting or basal levels of locomotion. However, methamphetamine-induced increase in locomotion was significantly reduced in Vglut2-cKO mice than in Vglut2-het control mice; 2) MPTP (20 mg/kg 4 with 2-hr injection interval, s.c.) caused more DA neuron death/loss in the SNc in Vglut2-cKO mice (80%) than in Vglut2-het control mice (40%), as assessed by TH-immunostaining, DA neuron counting, and tissue DA/DOPAC contents in both the striatum and SNc; Similarly, 3) intra-striatal microinjection of 6-OHDA also caused more DA terminal degeneration in the striatum in Vglut2-cKO mice than in Vglut2-het mice, as assessed by TH-immunostaining; Furthermore, 4) behavioral assays suggest that MPTP caused more severe impairment in rotarod locomotor performance and a larger reduction in locomotor activity in Vglut2-cKO mice than in Vglut2-het mice. These findings suggest that deletion of Vglut2 in DA neurons increases DA neuron susceptibility (toxicity) to the neurotoxins MPTP or 6-OHDA. To further confirm this finding, we will use transgenic techniques to increase Vglut2 expression in midbrain DA neurons in the future study to determine whether increased Vglut2 expression in midbrain DA neurons will produce a neuroprotective effect against MPTP- or 6-OHDA-induced DA neuron injury.