Krasnoyarsk State Medical University named after Prof. V.F. Voino-Yasenetsky, Research Institute of Molecular Medicine and Pathobiochemistry, Partizan Zheleznyak st. 1, 660022 Krasnoyarsk, Russia.
Krasnoyarsk State Medical University named after Prof. V.F. Voino-Yasenetsky, Department of Biological Chemistry, Medical Pharmaceutical and Toxicological Chemistry, Partizan Zheleznyak st., 1, 660022 Krasnoyarsk, Russia.
Neurobiol Dis. 2021 Jul;154:105340. doi: 10.1016/j.nbd.2021.105340. Epub 2021 Mar 19.
Bergmann glia (BG) are highly specialized radial astrocytes of the cerebellar cortex, which play a key role in the uptake of synaptic glutamate via the excitatory amino acid transporter EAAT1. Multiple lines of evidence suggest that in cerebellar neurodegenerative diseases reactive BG has a negative impact on neuronal function and survival through compromised EAAT activity. A family of such diseases are those caused by expansion of CAG repeats in genes of the ataxin family, resulting in spinocerebellar ataxias (SCA). We investigated the contribution of BG to the pathogenesis of cerebellar neurodegeneration in a model of SCA1, which was induced by expression of a polyglutamine mutant of ataxin-1 (ATXN1[Q85]) in BG specifically. We compared the outcomes with a novel model where we triggered excitotoxicity by a chronic optogenetic activation of BG with channelrhodopsin-2 (ChR2). In both cases we detected evidence of reduced glutamate uptake manifested by prolongation of excitatory postsynaptic currents in Purkinje cells which is consistent with documented reduction of expression and/or function of EAAT1. In both models we detected astroglyosis and Purkinje cells atrophy. Finally, the same pattern was detected in a knock-in mouse which expresses a polyglutamine mutant ataxin-1 ATXN1[Q154] in a non-cell-selective manner. Our results suggest that ATXN1[Q85] and ChR2-induced insult targeted to BG closely mimics SCA1 pathology, where excessive glutamate signaling appears to be a common feature likely being an important contributor to cerebellar neurodegeneration.
伯格曼胶质细胞（BG）是小脑皮层高度特化的放射状星形胶质细胞，通过兴奋性氨基酸转运体 EAAT1 摄取突触谷氨酸发挥关键作用。多条证据表明，在小脑神经退行性疾病中，反应性 BG 通过降低 EAAT 活性对神经元功能和存活产生负面影响。此类疾病家族包括由共济失调蛋白家族基因中 CAG 重复扩展引起的疾病，导致脊髓小脑共济失调（SCA）。我们通过在 BG 中特异性表达共济失调蛋白-1（ATXN1[Q85]）的多聚谷氨酰胺突变体来研究 BG 对 SCA1 小脑神经退行性变发病机制的贡献。我们将结果与一种新型模型进行了比较，该模型通过慢性光遗传学激活 BG 中的通道视紫红质-2（ChR2）来引发兴奋性毒性。在这两种情况下，我们都发现了谷氨酸摄取减少的证据，表现为浦肯野细胞中兴奋性突触后电流延长，这与 EAAT1 表达和/或功能的减少一致。在这两种模型中，我们都检测到了星形胶质细胞增生和浦肯野细胞萎缩。最后，在以非细胞选择性方式表达多聚谷氨酰胺突变体 ATXN1[Q154]的 knock-in 小鼠中也检测到了相同的模式。我们的结果表明，靶向 BG 的 ATXN1[Q85]和 ChR2 诱导的损伤非常类似于 SCA1 病理学，其中过量的谷氨酸信号似乎是一个共同特征，可能是小脑神经退行性变的一个重要贡献因素。
