Progressive neuronal loss is a hallmark feature distinguishing neurodegenerative diseases from normal aging. However, the underlying mechanisms remain unknown. Extracellular K+ homeostasis is a potential mediator of neuronal injury since K+ elevations increase excitatory activity. The dysregulation of extracellular K+ and potassium channel expressions during neurodegeneration could contribute to this distinction. We here measured the cortical extracellular K+ concentration ([K+]e) in awake wildtype mice as well as murine models of neurodegeneration using K+-sensitive microelectrodes. Unexpectedly, aged wildtype mice exhibited significantly lower cortical [K+]e than young mice. In contrast, cortical [K+]e was consistently elevated in Alzheimer’s disease (AD) (APP/PS1), amyotrophic lateral sclerosis (ALS) (SOD1G93A), and Huntington’s disease (HD) (R6/2) models. Cortical resting [K+]e correlated inversely with neuronal density and the [K+]e buffering rate but correlated positively with the predicted neuronal firing rate. Screening of astrocyte-selective genomic datasets revealed a number of potassium channel genes that were downregulated in these disease models but not in normal aging. In particular, the inwardly rectifying potassium channel Kcnj10 was downregulated in ALS and HD models but not in normal aging, while Fxyd1 and Slc1a3, each of which acts as a negative regulator of potassium uptake, were each upregulated by astrocytes in both AD and ALS models. Chronic elevation of [K+]e in response to changes in gene expression and the attendant neuronal hyperexcitability may drive the neuronal loss characteristic of these neurodegenerative diseases. These observations suggest that the dysregulation of extracellular K+ homeostasis in a number of neurodegenerative diseases could be due to aberrant astrocytic K+ buffering, and as such highlight a fundamental role for glial dysfunction in neurodegeneration.

中文翻译：

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细胞外钾的失调区分健康衰老和神经退行性变

进行性神经元损失是区分神经退行性疾病和正常衰老的标志特征。然而，潜在的机制仍然未知。细胞外 K+ 稳态是神经元损伤的潜在介质，因为 K+ 升高会增加兴奋性活动。神经变性期间细胞外 K+ 和钾通道表达的失调可能导致了这种区别。我们在这里使用 K+ 敏感微电极测量了清醒野生型小鼠以及神经变性小鼠模型的皮质细胞外 K+ 浓度 ([K+]e)。出乎意料的是，老年野生型小鼠的皮质 [K+]e 显着低于年轻小鼠。相比之下，在阿尔茨海默病 (AD) (APP/PS1)、肌萎缩侧索硬化症 (ALS) (SOD1G93A) 和亨廷顿病 (HD) (R6/2) 模型中，皮质 [K+]e 持续升高。皮质静息 [K+]e 与神经元密度和 [K+]e 缓冲率呈负相关，但与预测的神经元放电率正相关。对星形胶质细胞选择性基因组数据集的筛选揭示了许多钾通道基因在这些疾病模型中下调，但在正常衰老中却没有下调。特别是，内向整流钾通道 Kcnj10 在 ALS 和 HD 模型中下调，但在正常衰老中没有下调，而 Fxyd1 和 Slc1a3（各自充当钾摄取的负调节因子）在 AD 和 ALS 模型中均被星形胶质细胞上调。基因表达变化引起的 [K+]e 慢性升高以及随之而来的神经元过度兴奋可能会导致这些神经退行性疾病的神经元损失特征。这些观察结果表明，许多神经退行性疾病中细胞外 K+ 稳态的失调可能是由于异常的星形细胞 K+ 缓冲造成的，因此凸显了神经胶质细胞功能障碍在神经退行性疾病中的基本作用。