Data from: Vesicular monoamine transporter 2 (VMAT2) level regulates MPTP vulnerability and clearance of excess dopamine in mouse striatal terminals

The vesicular monoamine transporter 2 (VMAT2) packages neurotransmitters for release during neurotransmission and sequesters toxicants into vesicles to prevent neuronal damage. In mice, low VMAT2 levels causes catecholaminergic cell loss and behaviors resembling Parkinson’s disease, while high levels of VMAT2 increase dopamine release and protect against dopaminergic toxicants. However, comparisons across these VMAT2 mouse genotypes were impossible due to the differing genetic background strains of the animals. Following back-crossing to a C57BL/6 line, we confirmed that mice with ~95% lower VMAT2 levels compared to wildtype (VMAT2-LO) display significantly reduced vesicular uptake, progressive dopaminergic terminal loss with aging, and exacerbated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. Conversely, VMAT2 overexpressing mice (VMAT2-HI) are protected from the loss of striatal terminals following MPTP treatment. We also provide evidence that enhanced vesicular filling in the VMAT2-HI mice modifies the handling of newly synthesized dopamine, indicated by changes in indirect measures of extracellular dopamine clearance. These results confirm the role of VMAT2 in the protection of vulnerable nigrostriatal dopamine neurons and may also provide new insight into the side effects of L-DOPA treatments in Parkinson’s disease.囊泡单胺转运体2（vesicular monoamine transporter 2, VMAT2）可在神经传递过程中包装待释放的神经递质，并将有毒物质隔离至囊泡内以避免神经元损伤。在小鼠模型中，VMAT2水平低下会导致儿茶酚胺能神经元丢失，并出现类似帕金森病的行为表型；而VMAT2水平升高则可增加多巴胺释放，对多巴胺能毒物产生防护作用。然而，此前由于不同实验动物的遗传背景品系存在差异，无法对不同VMAT2基因型的小鼠进行对比研究。本研究通过将相关品系回交至C57BL/6品系后证实：与野生型相比VMAT2水平降低约95%的小鼠（VMAT2-LO），其囊泡摄取能力显著下降，随衰老出现进行性多巴胺能神经末梢丢失，且对1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）的毒性易感性加剧。与之相反，VMAT2过表达小鼠（VMAT2-HI）在接受MPTP处理后，纹状体神经末梢的丢失情况得到防护。本研究同时证实，VMAT2-HI小鼠中增强的囊泡充盈可改变新合成多巴胺的代谢过程，这一现象可通过细胞外多巴胺清除的间接检测指标变化得到体现。上述结果验证了VMAT2对脆弱的黑质纹状体多巴胺能神经元的保护作用，同时也可为帕金森病左旋多巴治疗的副作用提供新的研究视角。