Altered synaptic and firing properties of cerebellar Purkinje cells in a mouse model of ARSACS
Altered synaptic and firing properties of cerebellar Purkinje cells in a mouse model of ARSACS
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DOI：
10.1113/jp275902
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发表时间：
2018-09-01
影响因子：
5.5
通讯作者：
Watt, Alanna J.
中科院分区：
文献类型：
--
作者：
Ady, Visou;Toscano-Marquez, Brenda;Watt, Alanna J.
常染色体隐性遗传性痉挛共济失调(ARSACS)是一种早发性神经退行性疾病，包括明显的进行性小脑功能障碍。ARSACS是由编码Sacsin蛋白的Sacs基因的常染色体隐性功能丧失突变引起的。为了更好地了解ARSACS的小脑病理生理学，我们研究了ARSACS小鼠模型SACS(-/-)小鼠的浦肯野细胞的突触和放电特性。我们发现，兴奋性突触驱动减少到囊(-/-)浦肯野细胞，浦肯野细胞的放电频率在出生后(P)40天降低，但不是规律性的，这是第一次报告共济失调症状的年龄。放电频率缺陷仅限于后来表现为浦肯野细胞死亡的前叶，而没有观察到浦肯野细胞未丢失的后叶。早在P20，在运动障碍表现出来之前，就观察到轻度的放电障碍，这表明小脑功能障碍需要达到临界水平才能出现运动协调。最后，我们观察到囊泡(-/-)小鼠小脑深部核(DCN)中浦肯野细胞对靶神经元的神经支配减少。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中小脑相关疾病的发生。
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.