Department of Biology, McGill University, Montréal, Canada.
Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada.
J Physiol. 2018 Sep;596(17):4253-4267. doi: 10.1113/JP275902. Epub 2018 Jul 19.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative human disease characterized in part by ataxia and Purkinje cell loss in anterior cerebellar lobules. A knock-out mouse model has been developed that recapitulates several features of ARSACS. Using this ARSACS mouse model, we report changes in synaptic input and intrinsic firing in cerebellar Purkinje cells, as well as in their synaptic output in the deep cerebellar nuclei. Changes in firing are observed in anterior lobules that later exhibit Purkinje cell death, but not in posterior lobules that do not. Our results show that both synaptic and intrinsic alterations in Purkinje cell properties likely contribute to disease manifestation in ARSACS; these findings resemble pathophysiological changes reported in several other ataxias.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that includes a pronounced and progressive cerebellar dysfunction. ARSACS is caused by an autosomal recessive loss-of-function mutation in the Sacs gene that encodes the protein sacsin. To better understand the cerebellar pathophysiology in ARSACS, we studied synaptic and firing properties of Purkinje cells from a mouse model of ARSACS, Sacs mice. We found that excitatory synaptic drive was reduced onto Sacs Purkinje cells, and that Purkinje cell firing rate, but not regularity, was reduced at postnatal day (P)40, an age when ataxia symptoms were first reported. Firing rate deficits were limited to anterior lobules that later display Purkinje cell death, and were not observed in posterior lobules where Purkinje cells are not lost. Mild firing deficits were observed as early as P20, prior to the manifestation of motor deficits, suggesting that a critical level of cerebellar dysfunction is required for motor coordination to emerge. Finally, we observed a reduction in Purkinje cell innervation onto target neurons in the deep cerebellar nuclei (DCN) in Sacs mice. Together, these findings suggest that multiple alterations in the cerebellar circuit including Purkinje cell input and output contribute to cerebellar-related disease onset in ARSACS.
查尔洛夫-萨格奈遗传性痉挛性共济失调（ARSACS）是一种早发性神经退行性人类疾病，其特征部分为小脑前叶的共济失调和浦肯野细胞丢失。已经开发出一种敲除小鼠模型，该模型再现了 ARSACS 的几个特征。使用这种 ARSACS 小鼠模型，我们报告了小脑浦肯野细胞的突触输入和内在放电以及它们在深部小脑核中的突触输出的变化。在随后出现浦肯野细胞死亡的前叶中观察到放电变化，但在后叶中则没有。我们的结果表明，浦肯野细胞特性中的突触和内在改变都可能导致 ARSACS 中的疾病表现；这些发现类似于几种其他共济失调中报告的病理生理变化。
查尔洛夫-萨格奈遗传性痉挛性共济失调（ARSACS）是一种早发性神经退行性疾病，包括明显而进行性的小脑功能障碍。ARSACS 是由 Sacs 基因的常染色体隐性失功能突变引起的，该基因编码 sacsin 蛋白。为了更好地理解 ARSACS 的小脑病理生理学，我们研究了 ARSACS 小鼠模型中 Sacs 小鼠浦肯野细胞的突触和放电特性。我们发现，兴奋突触传入到 Sacs 浦肯野细胞减少，浦肯野细胞放电率在出生后第 40 天（P40）降低，此时首次报告了共济失调症状。放电率缺陷仅限于后来显示浦肯野细胞死亡的前叶，而在后叶中则没有观察到，后叶中浦肯野细胞不会丢失。早在运动缺陷出现之前的 P20 就观察到轻度放电缺陷，这表明需要小脑功能的临界水平才能出现运动协调。最后，我们观察到 Sacs 小鼠中深部小脑核（DCN）中浦肯野细胞传入到靶神经元的减少。总之，这些发现表明，小脑回路中的多种改变，包括浦肯野细胞的输入和输出，都有助于 ARSACS 中与小脑相关的疾病发作。
