Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 101 Woodruff Circle, WMB 6304, Atlanta, GA 30322, USA.
Department of Neurology, Emory University School of Medicine, 101 Woodruff Circle, WMB 6304, Atlanta, GA 30322, USA; Department of Human Genetics, Emory University School of Medicine, 101 Woodruff Circle, WMB 6300, Atlanta, GA 30322, USA; Department of Pediatrics, Emory University School of Medicine, 101 Woodruff Circle, WMB 6300, Atlanta, GA 30322, USA.
Neurobiol Dis. 2021 Jul;155:105369. doi: 10.1016/j.nbd.2021.105369. Epub 2021 Apr 21.
TOR1A-associated dystonia, otherwise known as DYT1 dystonia, is an inherited dystonia caused by a three base-pair deletion in the TOR1A gene (TOR1AΔE). Although the mechanisms underlying the dystonic movements are largely unknown, abnormalities in striatal dopamine and acetylcholine neurotransmission are consistently implicated whereby dopamine release is reduced while cholinergic tone is increased. Because striatal cholinergic neurotransmission mediates dopamine release, it is not known if the dopamine release deficit is mediated indirectly by abnormal acetylcholine neurotransmission or if Tor1a(ΔE) acts directly within dopaminergic neurons to attenuate release. To dissect the microcircuit that governs the deficit in dopamine release, we conditionally expressed Tor1a(ΔE) in either dopamine neurons or cholinergic interneurons in mice and assessed striatal dopamine release using ex vivo fast scan cyclic voltammetry or dopamine efflux using in vivo microdialysis. Conditional expression of Tor1a(ΔE) in cholinergic neurons did not affect striatal dopamine release. In contrast, conditional expression of Tor1a(ΔE) in dopamine neurons reduced dopamine release to 50% of normal, which is comparable to the deficit in Tor1a knockin mice that express the mutation ubiquitously. Despite the deficit in dopamine release, we found that the Tor1a(ΔE) mutation does not cause obvious nerve terminal dysfunction as other presynaptic mechanisms, including electrical excitability, vesicle recycling/refilling, Ca signaling, D2 dopamine autoreceptor function and GABA receptor function, are intact. Although the mechanistic link between Tor1a(ΔE) and dopamine release is unclear, these results clearly demonstrate that the defect in dopamine release is caused by the action of the Tor1a(ΔE) mutation within dopamine neurons.
TOR1A 相关的肌张力障碍，也称为 DYT1 肌张力障碍，是一种由 TOR1A 基因（TOR1AΔE）中三个碱基对缺失引起的遗传性肌张力障碍。尽管导致肌张力障碍运动的机制在很大程度上尚不清楚，但纹状体多巴胺和乙酰胆碱神经递质的异常一直被牵连，其中多巴胺释放减少，而胆碱能张力增加。由于纹状体胆碱能神经递质介导多巴胺释放，因此尚不清楚多巴胺释放缺陷是否是由异常乙酰胆碱神经递质间接介导的，或者 Tor1a(ΔE) 是否直接作用于多巴胺神经元以减弱释放。为了剖析调节多巴胺释放缺陷的微电路，我们在小鼠中条件性表达 Tor1a(ΔE) 在多巴胺神经元或胆碱能中间神经元中，并使用离体快速扫描循环伏安法评估纹状体多巴胺释放，或使用体内微透析评估多巴胺外排。Tor1a(ΔE) 在胆碱能神经元中的条件表达不会影响纹状体多巴胺释放。相比之下，Tor1a(ΔE) 在多巴胺神经元中的条件表达将多巴胺释放减少到正常水平的 50%，这与在普遍表达突变的 Tor1a 敲入小鼠中观察到的缺陷相当。尽管多巴胺释放减少，但我们发现 Tor1a(ΔE) 突变不会导致明显的神经末梢功能障碍，因为其他突触前机制，包括电兴奋性、囊泡回收/再填充、Ca 信号、D2 多巴胺自身受体功能和 GABA 受体功能都完好无损。尽管 Tor1a(ΔE) 和多巴胺释放之间的机制联系尚不清楚，但这些结果清楚地表明，多巴胺释放缺陷是由 Tor1a(ΔE) 突变在多巴胺神经元中的作用引起的。
