BACKGROUND Purkinje cells play a central role in establishing the cerebellar circuit. Accordingly, disrupting Purkinje cell development impairs cerebellar morphogenesis and motor function. In the Car8wdl mouse model of hereditary ataxia, severe motor deficits arise despite the cerebellum overcoming initial defects in size and morphology. METHODS To resolve how this compensation occurs, we asked how the loss of carbonic anhydrase 8 (CAR8), a regulator of IP3R1 Ca2+ signaling in Purkinje cells, alters cerebellar development in Car8wdl mice. Using a combination of histological, physiological, and behavioral analyses, we determined the extent to which the loss of CAR8 affects cerebellar anatomy, neuronal firing, and motor coordination during development. RESULTS Our results reveal that granule cell proliferation is reduced in early postnatal mutants, although by the third postnatal week there is enhanced and prolonged proliferation, plus an upregulation of Sox2 expression in the inner EGL. Modified circuit patterning of Purkinje cells and Bergmann glia accompany these granule cell adjustments. We also find that although anatomy eventually normalizes, the abnormal activity of neurons and muscles persists. CONCLUSIONS Our data show that losing CAR8 only transiently restricts cerebellar growth, but permanently damages its function. These data support two current hypotheses about cerebellar development and disease: (1) Sox2 expression may be upregulated at sites of injury and contribute to the rescue of cerebellar structure and (2) transient delays to developmental processes may precede permanent motor dysfunction. Furthermore, we characterize waddles mutant mouse morphology and behavior during development and propose a Sox2-positive, cell-mediated role for rescue in a mouse model of human motor diseases.

中文翻译：

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尽管在Car8蹒跚突变小鼠中平衡了小脑的形态发生，但仍存在持续的运动功能障碍。

背景技术浦肯野细胞在建立小脑回路中起核心作用。因此，破坏浦肯野细胞发育会损害小脑形态发生和运动功能。在遗传性共济失调的Car8wdl小鼠模型中，尽管小脑克服了大小和形态的初始缺陷，但仍出现严重的运动缺陷。方法为了解决这种补偿的发生方式，我们询问了碳酸酐酶8（CAR8）（Purkinje细胞中IP3R1 Ca2 +信号的调节剂）的损失如何改变Car8wdl小鼠的小脑发育。结合组织学，生理学和行为学分析，我们确定了CAR8丢失在多大程度上影响小脑解剖结构，神经元放电和运动协调。结果我们的结果表明，早期产后突变体中颗粒细胞的增殖减少，尽管到产后第三周，细胞的增殖得以增强和延长，并且内EGL中的Sox2表达上调。这些颗粒细胞调整伴随着Purkinje细胞和Bergmann胶质细胞的修饰电路图案。我们还发现，尽管解剖结构最终恢复了正常，但神经元和肌肉的异常活动仍然存在。结论我们的数据表明，丢失CAR8只会暂时限制小脑的生长，但会永久性损害其功能。这些数据支持有关小脑发育和疾病的两个当前假说：（1）Sox2表达可能在损伤部位上调，并有助于小脑结构的抢救；（2）发育过程的短暂延迟可能在永久性运动功能障碍之前。此外，