Department of Neuroscience, University Tor Vergata, Rome, Italy.
PLoS One. 2011;6(9):e24261. doi: 10.1371/journal.pone.0024261. Epub 2011 Sep 2.
DYT1 dystonia, a severe form of genetically determined human dystonia, exhibits reduced penetrance among carriers and begins usually during adolescence. The reasons for such age dependence and variability remain unclear.
We characterized the alterations in D2 dopamine receptor (D2R) signalling in striatal cholinergic interneurons at different ages in mice overexpressing human mutant torsinA (hMT). An abnormal excitatory response to the D2R agonist quinpirole was recorded at postnatal day 14, consisting of a membrane depolarization coupled to an increase in spiking frequency, and persisted unchanged at 3 and 9 months in hMT mice, compared to mice expressing wild-type human torsinA and non-transgenic mice. This response was blocked by the D2R antagonist sulpiride and depended upon G-proteins, as it was prevented by intrapipette GDP-β-S. Patch-clamp recordings from dissociated interneurons revealed a significant increase in the Cav2.2-mediated current fraction at all ages examined. Consistently, chelation of intracellular calcium abolished the paradoxical response to quinpirole. Finally, no gross morphological changes were observed during development.
These results suggest that an imbalanced striatal dopaminergic/cholinergic signaling occurs early in DYT1 dystonia and persists along development, representing a susceptibility factor for symptom generation.
DYT1 型肌张力障碍是一种严重的遗传性人类肌张力障碍，其在携带者中的表现为不完全外显，且通常在青春期开始。导致这种年龄依赖性和可变性的原因尚不清楚。
我们在过表达人突变 torsinA（hMT）的小鼠中，在不同年龄时研究纹状体胆碱能中间神经元中 D2 多巴胺受体（D2R）信号的改变。在出生后第 14 天记录到异常的 D2R 激动剂喹吡罗兴奋反应，其由膜去极化伴随着频率增加的尖峰组成，并且在 hMT 小鼠中与表达野生型人 torsinA 的小鼠和非转基因小鼠相比，在 3 个月和 9 个月时保持不变。这种反应被 D2R 拮抗剂舒必利阻断，并且依赖于 G 蛋白，因为它可以通过内管 GDP-β-S 来预防。从分离的中间神经元的膜片钳记录中发现，在所有检查的年龄中，Cav2.2 介导的电流分数显著增加。一致地，细胞内钙螯合消除了对喹吡罗的反常反应。最后，在发育过程中未观察到明显的形态变化。
这些结果表明，DYT1 型肌张力障碍中存在不平衡的纹状体多巴胺能/胆碱能信号传递，并且在整个发育过程中持续存在，这是产生症状的易感因素。
