We performed a comprehensive study of the morphological, functional, and genetic features of moonwalker (MWK) mice, a mouse model of spinocerebellar ataxia caused by a gain of function of the TRPC3 channel. These mice show numerous behavioral symptoms including tremor, altered gait, circling behavior, impaired motor coordination, impaired motor learning and decreased limb strength. Cerebellar pathology is characterized by early and almost complete loss of unipolar brush cells as well as slowly progressive, moderate loss of Purkinje cell (PCs). Structural damage also includes loss of synaptic contacts from parallel fibers, swollen ER structures, and degenerating axons. Interestingly, no obvious correlation was observed between PC loss and severity of the symptoms, as the phenotype stabilizes around 2 months of age, while the cerebellar pathology is progressive. This is probably due to the fact that PC function is severely impaired much earlier than the appearance of PC loss. Indeed, PC firing is already impaired in 3 weeks old mice. An interesting feature of the MWK pathology that still remains to be explained consists in a strong lobule selectivity of the PC loss, which is puzzling considering that TRPC is expressed in every PC. Intriguingly, genetic analysis of MWK cerebella shows, among other alterations, changes in the expression of both apoptosis inducing and resistance factors possibly suggesting that damaged PCs initiate specific cellular pathways that protect them from overt cell loss.

中文翻译：

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共济失调模型月球行者小鼠的表型、基因型和病理特征

我们对 Moonwalker (MWK) 小鼠的形态、功能和遗传特征进行了全面研究，MWK 小鼠是一种由 TRPC3 通道功能获得引起的脊髓小脑共济失调小鼠模型。这些小鼠表现出许多行为症状，包括震颤、步态改变、转圈行为、运动协调受损、运动学习受损和肢体力量下降。小脑病理学的特征是单极刷状细胞早期且几乎完全丧失，以及浦肯野细胞 (PC) 缓慢进展、中度丧失。结构损伤还包括平行纤维突触接触丧失、内质网结构肿胀和轴突退化。有趣的是，PC 丢失和症状严重程度之间没有观察到明显的相关性，因为表型在 2 个月左右稳定下来，而小脑病理学是进行性的。这可能是由于 PC 功能严重受损的时间早于 PC 丧失的出现。事实上，三周大的小鼠的 PC 放电已经受损。 MWK 病理学的一个有趣特征仍有待解释，即 PC 丢失的强小叶选择性，考虑到 TRPC 在每个 PC 中表达，这是令人费解的。有趣的是，MWK 小脑的遗传分析显示，除其他改变外，细胞凋亡诱导因子和抵抗因子的表达发生变化，这可能表明受损的 PC 启动了特定的细胞途径，保护它们免受明显的细胞损失。