Characterization of the direct pathway in Dyt1 ΔGAG heterozygous knock-in mice and dopamine receptor 1-expressing-cell-specific Dyt1 conditional knockout mice.
Characterization of the direct pathway in Dyt1 ΔGAG heterozygous knock-in mice and dopamine receptor 1-expressing-cell-specific Dyt1 conditional knockout mice.
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DOI：
10.1016/j.bbr.2021.113381
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发表时间：
2021-08-06
影响因子：
2.7
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Yokoi F;Chen HX;Oleas J;Dang MT;Xing H;Dexter KM;Li Y
DYT1肌张力障碍是一种主要由编码torsinA的DYT1 （TOR1A）的三核苷酸缺失（ΔGAG）引起的运动障碍。DYT1肌张力障碍患者纹状体与多巴胺受体1 （D1R）和2 （D2R）的配体结合活性有降低的趋势。Dyt1 ΔGAG敲入（KI）小鼠，具有相应的ΔGAG缺失，同样表现出纹状体D1R和d2r结合活性及其表达水平降低。虽然D2R降低的后果已被很好地描述，但对D1R降低的影响知之甚少。本研究检测了Dyt1 KI小鼠对D1R和D2R拮抗剂的运动反应。Dyt1 KI小鼠对D1R拮抗剂SCH 23390和D2R拮抗剂raclopride的反应性明显降低。电生理记录显示，Dyt1 KI小鼠纹状体表达d1r的中棘神经元的成对脉冲比显著增加，突触后微兴奋性电流发生改变。为了进一步分析体内torsinA在表达d1r的神经元中的功能，我们在这些神经元中产生Dyt1条件敲除（Dyt1 d1KO）小鼠。在梁行走试验中，Dyt1 d1KO小鼠自发运动活动减少，滑倒次数减少。Dyt1 d1KO雄性小鼠步态异常。Dyt1 d1KO小鼠显示纹状体D1R成熟缺陷。突变纹状体表达d1r的中棘神经元电容量增加，sEPSC频率降低，固有兴奋性降低。结果表明，表达d1r的细胞中的torsinA在电生理功能和运动性能中起重要作用。直接途径的医疗干预可能会影响这种疾病的发病和症状。
DYT1 dystonia is a movement disorder mainly caused by a trinucleotide deletion (ΔGAG) in DYT1 (TOR1A), coding for torsinA. DYT1 dystonia patients show trends of decreased striatal ligand-binding activities to dopamine receptors 1 (D1R) and 2 (D2R). Dyt1 ΔGAG knock-in (KI) mice, which have the corresponding ΔGAG deletion, similarly exhibit reduced striatal D1R and D2R-binding activities and their expression levels. While the consequences of D2R reduction have been well characterized, relatively little is known about the effect of D1R reduction. Here, locomotor responses to D1R and D2R antagonists were examined in Dyt1 KI mice. Dyt1 KI mice showed significantly less responsiveness to both D1R antagonist SCH 23390 and D2R antagonist raclopride. The electrophysiological recording indicated that Dyt1 KI mice showed a significantly increased paired-pulse ratio of the striatal D1R-expressing medium spiny neurons and altered miniature excitatory postsynaptic currents. To analyze the in vivo torsinA function in the D1R-expressing neurons further, Dyt1 conditional knockout (Dyt1 d1KO) mice in these neurons were generated. Dyt1 d1KO mice had decreased spontaneous locomotor activity and reduced numbers of slips in the beam-walking test. Dyt1 d1KO male mice showed abnormal gait. Dyt1 d1KO mice showed defective striatal D1R maturation. Moreover, the mutant striatal D1R-expressing medium spiny neurons had increased capacitance, decreased sEPSC frequency, and reduced intrinsic excitability. The results suggest that torsinA in the D1R-expressing cells plays an important role in the electrophysiological function and motor performance. Medical interventions to the direct pathway may affect the onset and symptoms of this disorder.
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影响因子：
8.6
作者：
Albanese, Alberto;Bhatia, Kailash;Bressman, Susan B.;DeLong, Mahlon R.;Fahn, Stanley;Fung, Victor S. C.;Hallett, Mark;Jankovic, Joseph;Jinnah, Hyder A.;Klein, Christine;Lang, Anthony E.;Mink, Jonathan W.;Teller, Jan K.
通讯作者：
Teller, Jan K.
影响因子：
2.7
作者：
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通讯作者：
Li, Yuqing
影响因子：
5.5
作者：
Debanne, D;Guerineau, NC;Thompson, SM
通讯作者：
Thompson, SM
影响因子：
3.3
作者：
Fernagut, PO;Diguet, E;Tison, F
通讯作者：
Tison, F
影响因子：
81.5
作者：
Balint, Bettina;Mencacci, Niccolo E.;Bhatia, Kailash P.
通讯作者：
Bhatia, Kailash P.