Huntington's disease (HD) is a progressive neurodegenerative disorder with no cure, characterized by significant neurodegeneration of striatal GABAergic medium spiny neurons (MSNs). Early stages of the disease are characterized by the loss of dopamine 2 receptor-expressing MSNs (D2 MSNs) followed by degeneration of dopamine 1 receptor-expressing MSNs (D1 MSNs), leading to aberrant basal ganglia signaling. While the early degeneration of D2 MSNs and impaired GABAergic transmission are well-documented, potassium chloride cotransporter 2 (KCC2), a key regulator of intracellular chloride (Cl-), and therefore GABAergic signaling, has not been characterized in D1 and D2 MSNs in HD. We aimed to investigate whether Cl- regulation was differentially altered in D1 and D2 MSNs and may contribute to the early degeneration of D2 MSNs in male and female symptomatic R6/2 mice. We used electrophysiology to record the reversal potential for GABAA receptors (EGABA), a read-out for the efficacy of Cl- regulation, in striatal D1 and D2 MSNs and their corresponding output structures. During the early symptomatic phase (P55-P65), Cl- impairments were observed in D2 MSNs in R6/2 mice, with no change in D1 MSNs. Cl- regulation was also dysfunctional in the globus pallidus externa, resulting in GABA-mediated excitation. When we overexpressed KCC2 in D2 MSNs using AAV-mediated delivery, we delayed the onset of motor impairments in R6/2 mice. We demonstrate that Cl- homeostasis is differentially altered in D1 and D2 MSNs and may contribute to the enhanced susceptibility of D2 MSNs during HD progression.Significance Statement Huntington's Disease is an inherited neurodegenerative disease caused by a repeat expansion in the Huntingtin gene and characterized by the sequential loss of dopamine 2 and dopamine 1 receptor-expressing medium spiny neurons (D2 and D1 MSNs) of the striatum. MSNs release GABA, which depends on proper Cl- regulation for inhibition. We asked whether Cl- homeostasis is differentially altered in D1 and D2 MSNs and their output structures, and whether this altered expression contributes to the pattern of degeneration between these two principal striatal cell types. Using electrophysiology, biochemistry, and fluorescence imaging, we determined that Cl- regulation was impaired in D2 MSNs in R6/2 mice, with no change in D1 MSNs. Cl- was also dysregulated in the globus pallidus externa resulting in excitatory GABA.

中文翻译：

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恢复 HD 小鼠模型的 D2 神经元中受损的 cl- 可以挽救运动障碍。


亨廷顿病 （HD） 是一种无法治愈的进行性神经退行性疾病，其特征是纹状体 GABA 能中棘神经元 （MSN） 的显著神经变性。疾病的早期阶段的特征是表达多巴胺 2 受体的 MSN （D2 MSN） 的缺失，随后表达多巴胺 1 受体的 MSN （D1 MSN） 变性，导致基底神经节信号异常。虽然 D2 MSN 的早期退化和 GABA 能传递受损有充分的文献证明，但氯化钾协同转运蛋白 2 （KCC2） 是细胞内氯离子 （Cl-） 的关键调节因子，因此是 GABA 能信号传导，尚未在 HD 的 D1 和 D2 MSN 中得到表征。我们旨在研究 D1 和 D2 MSN 中的 Cl- 调节是否发生差异改变，并可能导致雄性和雌性症状性 R6/2 小鼠 D2 MSN 的早期退化。我们使用电生理学记录了纹状体 D1 和 D2 MSN 中 GABAA 受体 （EGABA） 的逆转电位，这是 Cl- 调节功效的读数及其相应的输出结构。在症状早期阶段 （P55-P65），在 R6/2 小鼠的 D2 MSN 中观察到 Cl- 损伤，D1 MSN 没有变化。Cl- 调节在苍白球外也功能障碍，导致 GABA 介导的兴奋。当我们使用 AAV 介导的递送在 D2 MSN 中过表达 KCC2 时，我们延迟了 R6/2 小鼠运动障碍的发生。我们证明 Cl- 稳态在 D1 和 D2 MSN 中发生差异改变，并可能导致 HD 进展期间 D2 MSN 的易感性增强。意义声明 亨廷顿舞蹈症是一种由亨廷顿基因重复扩增引起的遗传性神经退行性疾病，其特征是纹状体表达多巴胺 2 和多巴胺 1 受体的中等棘神经元（D2 和 D1 MSN）连续丢失。MSN 释放 GABA，它依赖于适当的 Cl- 调节进行抑制。我们询问了 D1 和 D2 MSN 及其输出结构中 Cl- 稳态是否发生差异改变，以及这种改变的表达是否有助于这两种主要纹状体细胞类型之间的变性模式。使用电生理学、生物化学和荧光成像，我们确定 R6/2 小鼠的 D2 MSN 中的 Cl- 调节受损，而 D1 MSN 没有变化。Cl- 在苍白球外表中也失调，导致兴奋性 GABA。