Subtle changes in Purkinje cell firing in Purkinje cell-specific Dyt1 ΔGAG knock-in mice.

Dystonia Pub Date : 2025-01-01 Epub Date: 2025-01-29 DOI:10.3389/dyst.2025.14148
Hong Xing, Pallavi Girdhar, Yuning Liu, Fumiaki Yokoi, David E Vaillancourt, Yuqing Li
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Abstract

DYT1 dystonia is an inherited early-onset generalized dystonia characterized by sustained muscle contractions causing abnormal, repetitive movements or postures. Most DYT1 patients have a heterozygous trinucleotide GAG deletion (ΔGAG) in DYT1/TOR1A, coding for torsinA. Dyt1 heterozygous ΔGAG knock-in (KI) mice or global KI mice show motor deficits and abnormal Purkinje cell firing. However, Purkinje cell-specific heterozygous ΔGAG conditional KI mice (Pcp2-KI) show improved motor performance, reduced sensory-evoked brain activation in the striatum and midbrain, and reduced functional connectivity of the striatum with the anterior medulla. Whether Pcp2-KI mice show similar abnormal Purkinje cell firing as the global KI mice, suggesting a cell-autonomous effect causes the abnormal Purkinje cell firing in the global KI mice, is unknown. We used acute cerebellar slice recording in Pcp2-KI mice to address this issue. The Pcp2-KI mice exhibited no changes in spontaneous firing and intrinsic excitability compared to the control mice. While membrane properties were largely unchanged, the resting membrane potential was slightly hyperpolarized, which was associated with decreased baseline excitability. Our results suggest that the abnormal Purkinje cell firing in the global KI mice was not cell-autonomous and was caused by physiological changes elsewhere in the brain circuits. Our results also contribute to the ongoing research of how basal ganglia and cerebellum interact to influence motor control in normal states and movement disorders.

浦肯野细胞特异性Dyt1 ΔGAG敲入小鼠中浦肯野细胞放电的细微变化。
DYT1肌张力障碍是一种遗传性早发全身性肌张力障碍,其特征是持续的肌肉收缩导致异常、重复的运动或姿势。大多数DYT1患者在编码torsinA的DYT1/TOR1A中存在杂合三核苷酸GAG缺失(ΔGAG)。Dyt1杂合ΔGAG敲入(KI)小鼠或全局KI小鼠表现出运动缺陷和异常的浦肯野细胞放电。然而,浦肯野细胞特异性杂合ΔGAG条件KI小鼠(Pcp2-KI)表现出改善的运动表现,纹状体和中脑的感觉诱发脑激活减少,纹状体与前髓质的功能连接减少。Pcp2-KI小鼠是否表现出与全球KI小鼠相似的异常浦肯野细胞放电,提示细胞自主效应导致全球KI小鼠的异常浦肯野细胞放电,尚不清楚。我们在Pcp2-KI小鼠中使用急性小脑切片记录来解决这个问题。与对照小鼠相比,Pcp2-KI小鼠的自发放电和内在兴奋性没有变化。虽然膜性质基本不变,但静息膜电位略微超极化,这与基线兴奋性降低有关。我们的研究结果表明,全球KI小鼠的异常浦肯野细胞放电不是细胞自主的,而是由脑回路其他地方的生理变化引起的。我们的结果也有助于正在进行的关于基底神经节和小脑如何相互作用影响正常状态和运动障碍的运动控制的研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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