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Dysregulation of extracellular potassium distinguishes healthy ageing from neurodegeneration

神经退行性变 老化 细胞外 神经科学 医学 生物 化学 细胞生物学 内科学 疾病 有机化学
作者
Fengfei Ding,Qian Sun,C. N. H. Long,Rune Rasmussen,Sisi Peng,Qiwu Xu,Ning Kang,Wei Song,Pia Weikop,Steven A. Goldman,Maiken Nedergaard
出处
期刊:Brain [Oxford University Press]
卷期号:147 (5): 1726-1739 被引量:5
标识
DOI:10.1093/brain/awae075
摘要

Abstract Progressive neuronal loss is a hallmark feature distinguishing neurodegenerative diseases from normal ageing. However, the underlying mechanisms remain unknown. Extracellular K+ homeostasis is a potential mediator of neuronal injury as K+ elevations increase excitatory activity. The dysregulation of extracellular K+ and potassium channel expressions during neurodegeneration could contribute to this distinction. Here we measured the cortical extracellular K+ concentration ([K+]e) in awake wild-type mice as well as murine models of neurodegeneration using K+-sensitive microelectrodes. Unexpectedly, aged wild-type mice exhibited significantly lower cortical [K+]e than young mice. In contrast, cortical [K+]e was consistently elevated in Alzheimer’s disease (APP/PS1), amyotrophic lateral sclerosis (ALS) (SOD1G93A) and Huntington’s disease (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 ageing. In particular, the inwardly rectifying potassium channel Kcnj10 was downregulated in ALS and Huntington’s disease models but not in normal ageing, while Fxyd1 and Slc1a3, each of which acts as a negative regulator of potassium uptake, were each upregulated by astrocytes in both Alzheimer’s disease 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.
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