Norman Fixel Institute for Neurological Diseases, Department of Neurology, College of Medicine, University of Florida, Gainesville, FL, United States; Genetics Institute, University of Florida, Gainesville, FL, United States.
Norman Fixel Institute for Neurological Diseases, Department of Neurology, College of Medicine, University of Florida, Gainesville, FL, United States.
Behav Brain Res. 2021 Apr 9;403:113137. doi: 10.1016/j.bbr.2021.113137. Epub 2021 Jan 18.
DYT1 or DYT-TOR1A dystonia is early-onset, generalized dystonia. Most DYT1 dystonia patients have a heterozygous trinucleotide GAG deletion in DYT1 or TOR1A gene, with a loss of a glutamic acid residue of the protein torsinA. DYT1 dystonia patients show reduced striatal dopamine D2 receptor (D2R) binding activity. We previously reported reduced striatal D2R proteins and impaired corticostriatal plasticity in Dyt1 ΔGAG heterozygous knock-in (Dyt1 KI) mice. It remains unclear how the D2R reduction contributes to the pathogenesis of DYT1 dystonia. Recent knockout studies indicate that D2R on cholinergic interneurons (Chls) has a significant role in corticostriatal plasticity, while D2R on medium spiny neurons (MSNs) plays a minor role. To determine how reduced D2Rs on ChIs and MSNs affect motor performance, we generated ChI- or MSN-specific D2R conditional knockout mice (Drd2 ChKO or Drd2 sKO). The striatal ChIs in the Drd2 ChKO mice showed an increased firing frequency and impaired quinpirole-induced inhibition, suggesting a reduced D2R function on the ChIs. Drd2 ChKO mice had an age-dependent deficient performance on the beam-walking test similar to the Dyt1 KI mice. The Drd2 sKO mice, conversely, had a deficit on the rotarod but not the beam-walking test. Our findings suggest that D2Rs on Chls and MSNs have critical roles in motor control and balance. The similarity of the beam-walking deficit between the Drd2 ChKO and Dyt1 KI mice supports our earlier notion that D2R reduction on striatal ChIs contributes to the pathophysiology and the motor symptoms of DYT1 dystonia.
DYT1 或 DYT-TOR1A 型肌张力障碍是一种早发性、全身性肌张力障碍。大多数 DYT1 型肌张力障碍患者在 DYT1 或 TOR1A 基因中存在 GAG 三核苷酸缺失的杂合子，导致蛋白 torsinA 中谷氨酸残基丢失。DYT1 型肌张力障碍患者表现出纹状体多巴胺 D2 受体（D2R）结合活性降低。我们之前报道过 Dyt1ΔGAG 杂合敲入（Dyt1KI）小鼠纹状体 D2R 蛋白减少和皮质纹状体可塑性受损。目前尚不清楚 D2R 减少如何导致 DYT1 型肌张力障碍的发病机制。最近的基因敲除研究表明，胆碱能中间神经元（Chls）上的 D2R 在皮质纹状体可塑性中具有重要作用，而中脑纹状体神经元（MSNs）上的 D2R 作用较小。为了确定 Chls 和 MSNs 上减少的 D2R 如何影响运动表现，我们生成了 ChI 或 MSN 特异性 D2R 条件性敲除小鼠（Drd2ChKO 或 Drd2sKO）。Drd2ChKO 小鼠纹状体 Chls 的放电频率增加，并且 quinpirole 诱导的抑制作用受损，提示 Chls 上的 D2R 功能降低。Drd2ChKO 小鼠在棒行走测试中表现出年龄依赖性的运动缺陷，与 Dyt1KI 小鼠相似。相反，Drd2sKO 小鼠在转棒实验中表现出缺陷，但在棒行走测试中没有缺陷。我们的研究结果表明，Chls 和 MSNs 上的 D2R 在运动控制和平衡中具有关键作用。Drd2ChKO 和 Dyt1KI 小鼠之间在棒行走缺陷上的相似性支持我们之前的观点，即纹状体 Chls 上的 D2R 减少有助于 DYT1 型肌张力障碍的病理生理学和运动症状。
