Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA.
Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA.
Exp Neurol. 2021 Sep;343:113783. doi: 10.1016/j.expneurol.2021.113783. Epub 2021 Jun 10.
DYT1 dystonia is a debilitating movement disorder characterized by repetitive, unintentional movements and postures. The disorder has been linked to mutation of the TOR1A/DYT1 gene encoding torsinA. Convergent evidence from studies in humans and animal models suggest that striatal medium spiny neurons and cholinergic neurons are important in DYT1 dystonia. What is not known is how torsinA dysfunction in these specific cell types contributes to the pathophysiology of DYT1 dystonia. In this study we sought to determine whether torsinA dysfunction in cholinergic neurons alone is sufficient to generate the sensorimotor dysfunction and brain changes associated with dystonia, or if torsinA dysfunction in a broader subset of cell types is needed. We generated two genetically modified mouse models, one with selective Dyt1 knock-out from dopamine-2 receptor expressing neurons (D2KO) and one where only cholinergic neurons are impacted (Ch2KO). We assessed motor deficits and performed in vivo 11.1 T functional MRI to assess sensory-evoked brain activation and connectivity, along with diffusion MRI to assess brain microstructure. We found that D2KO mice showed greater impairment than Ch2KO mice, including reduced sensory-evoked brain activity in key regions of the sensorimotor network, and altered functional connectivity of the striatum that correlated with motor deficits. These findings suggest that (1) the added impact of torsinA dysfunction in medium spiny and dopaminergic neurons of the basal ganglia generate more profound deficits than the dysfunction of cholinergic neurons alone, and (2) that sensory network impairments are linked to motor deficits in DYT1 dystonia.
DYT1 型肌张力障碍是一种使人衰弱的运动障碍疾病，其特征是出现重复、无意识的运动和姿势。该疾病与编码 torsinA 的 TOR1A/DYT1 基因突变有关。来自人类和动物模型的研究的一致性证据表明，纹状体中间神经元和胆碱能神经元在 DYT1 型肌张力障碍中起重要作用。目前尚不清楚 torsinA 在这些特定细胞类型中的功能障碍如何导致 DYT1 型肌张力障碍的病理生理学改变。在这项研究中，我们试图确定仅在胆碱能神经元中 torsinA 功能障碍是否足以产生与肌张力障碍相关的感觉运动功能障碍和大脑变化，或者是否需要更广泛的细胞类型中 torsinA 功能障碍。我们生成了两种基因修饰的小鼠模型，一种是多巴胺-2 受体表达神经元中特异性 Dyt1 敲除的模型（D2KO），另一种是仅影响胆碱能神经元的模型（Ch2KO）。我们评估了运动缺陷，并进行了体内 11.1T 功能磁共振成像（fMRI）以评估感觉诱发的大脑激活和连通性，以及弥散磁共振成像（dMRI）以评估大脑微观结构。我们发现，D2KO 小鼠比 Ch2KO 小鼠表现出更大的损伤，包括感觉诱发的大脑活动在感觉运动网络的关键区域减少，以及纹状体的功能连通性改变，与运动缺陷相关。这些发现表明：（1）基底神经节中的中间神经元和多巴胺能神经元中 torsinA 功能障碍的附加影响比单独的胆碱能神经元功能障碍产生更严重的缺陷；（2）感觉网络的损伤与 DYT1 型肌张力障碍的运动缺陷有关。
