Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224.
Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224;
Proc Natl Acad Sci U S A. 2018 Dec 4;115(49):E11532-E11541. doi: 10.1073/pnas.1800886115. Epub 2018 Nov 15.
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.
中脑多巴胺 (DA) 神经元的亚群表达囊泡谷氨酸转运体 2 (VgluT2),促进谷氨酸的突触囊泡装载。最近的研究表明,这种表达可以调节多巴胺依赖性的奖励行为,但对于像帕金森病 (PD) 这样的神经退行性疾病中 DA 神经元 VgluT2 表达的功能后果知之甚少。在这里,我们报告说,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 神经元中谷氨酸的释放,降低了其脑源性神经营养因子 (BDNF) 和酪氨酸受体激酶 B (TrkB) 的表达,并加剧了暴露于神经毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 的病理影响。此外,病毒拯救 VglutT2-cKO 小鼠中 DA 神经元中的 VgluT2 表达恢复了 BDNF/TrkB 表达,并减轻了 MPTP 诱导的 DA 神经元丢失和运动障碍。总之,这些发现表明 DA 神经元中 VgluT2 的表达具有神经保护作用。导致 DA 神经元中 VgluT2 表达减少或功能降低的遗传或环境因素可能会使一些人面临更大的 DA 神经元退化风险。因此,维持 DA 神经元中 VgluT2 的生理表达和功能可能代表着开发 PD 预防性治疗干预措施的一个有效分子靶点。