Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
Department of Biomedical Engineering and Health Systems, KTH Royal Institute of Technology, Huddinge, Sweden.
Neuropathol Appl Neurobiol. 2023 Feb;49(1):e12867. doi: 10.1111/nan.12867.
CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia.
The rotarod, paw-print and beam-walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild-type mice were quantified by 9.4T gadolinium-enhanced post-mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam-walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride.
CYP2C19 transgenic mice exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips in the beam-walking test; the motoric phenotype was more pronounced in youth. Transgenic mice exhibited a profound reduction of 12% in cerebellar volume and a moderate reduction of 4% in hippocampal volume; both regions exhibited an increased antioxidative enzyme activity. CYP2C19 mice were hyperdopaminergic; however, the motoric impairment was not ameliorated by dopamine receptor antagonists, and there was no alteration in the number of midbrain dopaminergic neurons in CYP2C19 mice.
Humanised CYP2C19 transgenic mice exhibit altered gait and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.
CYP2C19 转基因小鼠在肝脏和发育中的大脑中表达人类 CYP2C19 基因，表现出与情绪和运动障碍相关的神经发育改变。由于新动物模型的验证对于理解运动障碍的病因和病理生理学至关重要，因此本研究的目的是描述 CYP2C19 转基因小鼠的运动表型，并探讨其作为新的共济失调动物模型的有效性。
利用转棒、爪印和平衡木试验来描述运动表型。通过 9.4T 钆增强死后结构神经影像学对 CYP2C19 转基因和野生型小鼠的 20 个脑区体积进行定量分析。通过生化方法定量测定抗氧化酶活性。通过色谱定量测定多巴胺及其代谢物的浓度，并进行随后的免疫组织化学分析来描述多巴胺能改变。在使用多巴胺受体拮抗剂 ecopipam 和 raclopride 进行治疗后，重复进行平衡木试验。
CYP2C19 转基因小鼠表现出异常的、单侧共济失调样步态、握持反射和平衡木试验中 5.6 倍的爪滑；在青少年中，运动表型更为明显。转基因小鼠小脑体积减少 12%，海马体积减少 4%；这两个区域的抗氧化酶活性都增加了。CYP2C19 小鼠表现出高多巴胺能；然而，多巴胺受体拮抗剂并不能改善运动障碍，并且 CYP2C19 小鼠的中脑多巴胺能神经元数量没有改变。
人源化 CYP2C19 转基因小鼠表现出异常的步态和功能性运动障碍；这种表型可能是由于小脑发育异常引起的。
