Diverse Mechanisms Lead to Common Dysfunction of Striatal Cholinergic Interneurons in Distinct Genetic Mouse Models of Dystonia
Diverse Mechanisms Lead to Common Dysfunction of Striatal Cholinergic Interneurons in Distinct Genetic Mouse Models of Dystonia
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DOI：
10.1523/jneurosci.0407-19.2019
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发表时间：
2019-09-04
影响因子：
5.3
通讯作者：
Standaert, David G.
中科院分区：
文献类型：
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作者：
Jaunarajs, Karen L. Eskow;Scarduzio, Mariangela;Standaert, David G.
临床和实验数据表明，肌张力障碍患者的纹状体胆碱能功能障碍，这是一种运动障碍，通常通过异常肌肉收缩导致扭曲的姿势。三种形式的孤立人类肌张力障碍是由TOR1A(DYT1)、THAP1(DYT6)和GNAL(DYT25)基因突变引起的。携带这些突变的实验模型有助于识别可能的共同细胞机制。最近，我们报道了DYT1(Delta gag/+)小鼠体内微透析升高细胞外纹状体乙酰胆碱和多巴胺D2受体(D2R)激动剂反常兴奋胆碱能中间神经元(CHI)的研究。这种矛盾的兴奋是由M受体(Mach Rs)过度激活引起的，导致D2R偶联从典型的G(i/o)信号切换到非典型的β-arrestin信号。我们试图确定DYT1(Delta gag/+)小鼠的这些机制是否与Thap1(C54)(Y/)(+)敲入和GNAL(+/-)敲除肌张力障碍模型相同，并确定性别的影响。我们发现thap1(C54)(Y/)(+)小鼠无论性别都有细胞外纹状体乙酰胆碱升高和D2R诱导的反常CHI兴奋，这种兴奋可被mAChR抑制逆转。在雄性和雌性GNAL(+/-)小鼠中，细胞外乙酰胆碱水平没有升高，但矛盾的D2R介导的CHI兴奋被保留，并仅被腺苷A2受体抑制所逆转。偏爱G(I/O)的D2R激动剂未能增加CHI的兴奋性，提示D2R偶联可能切换到β-arrestin，就像以前在DYT1模型中看到的那样。这些数据表明，虽然在这些人类肌张力障碍的遗传模型中并不总是检测到细胞外乙酰胆碱水平的升高，但D2R介导的CHI的矛盾兴奋是共同的，并且是由不同的G蛋白偶联受体的功能改变引起的。
Clinical and experimental data indicate striatal cholinergic dysfunction in dystonia, a movement disorder typically resulting in twisted postures via abnormal muscle contraction. Three forms of isolated human dystonia result from mutations in the TOR1A (DYT1), THAP1 (DYT6), and GNAL (DYT25) genes. Experimental models carrying these mutations facilitate identification of possible shared cellular mechanisms. Recently, we reported elevated extracellular striatal acetylcholine by in vivo microdialysis and paradoxical excitation of cholinergic interneurons (ChIs) by dopamine D2 receptor (D2R) agonism using ex vivo slice electrophysiology in Dyt1(Delta GAG/+) mice. The paradoxical excitation was caused by overactive muscarinic receptors (mACh Rs), leading to a switch in D2R coupling from canonical G(i/o) to noncanonical beta-arrestin signaling. We sought to determine whether these mechanisms in Dyt1(Delta GAG/+) mice are shared with Thap1(C54)(Y/)(+) knock-in and Gnal(+/-) knock-out dystonia models and to determine the impact of sex. We found Thap1(C54)(Y/)(+) mice of both sexes have elevated extracellular striatal acetylcholine and D2R-induced paradoxical ChI excitation, which was reversed by mAChR inhibition. Elevated extracellular acetylcholine was absent in male and female Gnal(+/-) mice, but the paradoxical D2R-mediated ChI excitation was retained and only reversed by inhibition of adenosine A2ARs. The G(i/o)-preferring D2R agonist failed to increase ChI excitability, suggesting a possible switch in coupling of D2Rs to beta-arrestin, as seen previously in a DYT1 model. These data show that, whereas elevated extracellular acetylcholine levels are not always detected across these genetic models of human dystonia, the D2R-mediated paradoxical excitation of ChIs is shared and is caused by altered function of distinct G-protein-coupled receptors.