A subset of midbrain dopamine (DA) neurons express vesicular glutamate transporter 2 (VgluT2), which facilitates synaptic vesicle loading of glutamate. Recent studies indicate that such expression can modulate DA-dependent reward behaviors, but little is known about functional consequences of DA neuron VgluT2 expression in neurodegenerative diseases like Parkinson's disease (PD). Here, we report that selective deletion of VgluT2 in DA neurons in conditional VgluT2-KO (VgluT2-cKO) mice abolished glutamate release from DA neurons, reduced their expression of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB), and exacerbated the pathological effects of exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, viral rescue of VgluT2 expression in DA neurons of VglutT2-cKO mice restored BDNF/TrkB expression and attenuated MPTP-induced DA neuron loss and locomotor impairment. Together, these findings indicate that VgluT2 expression in DA neurons is neuroprotective. Genetic or environmental factors causing reduced expression or function of VgluT2 in DA neurons may place some individuals at increased risk for DA neuron degeneration. Therefore, maintaining physiological expression and function of VgluT2 in DA neurons may represent a valid molecular target for the development of preventive therapeutic interventions for PD.

中文翻译：

---

多巴胺神经元中囊泡谷氨酸转运蛋白的基因缺失增加了小鼠对MPTP诱导的神经毒性的脆弱性。

中脑多巴胺（DA）神经元的子集表达水泡谷氨酸转运蛋白2（VgluT2），这有助于谷氨酸的突触小泡负载。最近的研究表明，这种表达可以调节DA依赖的奖励行为，但对于神经变性疾病（如帕金森氏病（PD））中DA神经元VgluT2表达的功能后果知之甚少。在这里，我们报道在条件性VgluT2-KO（VgluT2-cKO）小鼠中DA神经元中VgluT2的选择性缺失消除了DA神经元释放的谷氨酸盐，降低了脑源性神经营养因子（BDNF）和酪氨酸受体激酶B（TrkB）的表达，并加剧了神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）暴露的病理影响。此外，病毒挽救VglutT2-cKO小鼠DA神经元中VgluT2表达的表达恢复了BDNF / TrkB表达，并减弱了MPTP诱导的DA神经元丧失和运动功能障碍。在一起，这些发现表明DA神经元中的VgluT2表达具有神经保护作用。导致DA神经元中VgluT2表达或功能降低的遗传或环境因素可能会使某些人的DA神经元变性风险增加。因此，在DA神经元中维持VgluT2的生理表达和功能可能代表了针对PD的预防性治疗干预措施发展的有效分子靶点。导致DA神经元中VgluT2表达或功能降低的遗传或环境因素可能会使某些人的DA神经元变性风险增加。因此，在DA神经元中维持VgluT2的生理表达和功能可能代表了针对PD的预防性治疗干预措施发展的有效分子靶点。导致DA神经元中VgluT2表达或功能降低的遗传或环境因素可能会使某些人的DA神经元变性风险增加。因此，在DA神经元中维持VgluT2的生理表达和功能可能代表了针对PD的预防性治疗干预措施发展的有效分子靶点。