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Cited by 592Genetic Neurodegenerative DiseasesNeuroscience and Neuropharmacology ResearchIon channel regulation and function

Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington's disease model mice

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Tong, Xiaoping, Ao, Yan, Faas, Guido C, Nwaobi, Sinifunanya E, Xu, Ji, Haustein, Martin D, Anderson, Mark A, Mody, Istvan +3 more·2014·Nature Neuroscience
DOI 10.1038/nn.3691PMC PMC4064471
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Abstract

Huntington's disease (HD) is characterized by striatal medium spiny neuron (MSN) dysfunction, but the underlying mechanisms remain unclear. We explored roles for astrocytes, in which mutant huntingtin is expressed in HD patients and mouse models. We found that symptom onset in R6/2 and Q175 HD mouse models was not associated with classical astrogliosis, but was associated with decreased Kir4.1 K(+) channel functional expression, leading to elevated in vivo striatal extracellular K(+), which increased MSN excitability in vitro. Viral delivery of Kir4.1 channels to striatal astrocytes restored Kir4.1 function, normalized extracellular K(+), ameliorated aspects of MSN dysfunction, prolonged survival and attenuated some motor phenotypes in R6/2 mice. These findings indicate that components of altered MSN excitability in HD may be caused by heretofore unknown disturbances of astrocyte-mediated K(+) homeostasis, revealing astrocytes and Kir4.1 channels as therapeutic targets.

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  • Functions lost or altered in reactive astrocytes include neurotransmitter and ion buffering in mouse HD models, communication via gap junctions in the sclerotic hippocampus of patients with epilepsy, phagocytic clearance of dystrophic neurites, and metabolic coupling by glycolysis-derived d-serine and lactate in mouse AD models.

    “Functions lost or altered in reactive astrocytes include neurotransmitter and ion buffering in mouse HD models58, communication via gap junctions in the sclerotic hippocampus of patients with epilepsy59, phagocytic clearance of dystrophic neurites60, and metabolic coupling by glycolysis-derived d-serine61 and lactate62 in mouse AD models.”

    From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [58]

    The Discussion reports reduced GLT-1 and Kir4.1 expression and impaired extracellular potassium maintenance in HD mouse models, supporting altered neurotransmitter and ion buffering. But it says these early functional changes occurred without astrogliosis; the Results likewise found little or no striatal astrogliosis at symptomatic ages. This source therefore does not support describing the affected astrocytes as reactive. (LLM, conf=0.90)

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Cited by

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Authors
Tong, X., Ao, Y., Faas, G. C., Nwaobi, S. E., Xu, J., Haustein, M. D., Anderson, M. A., Mody, I., Olsen, M. L., Sofroniew, M. V., & Khakh, B. S.
Affiliations
  • University of California, Los Angeles (US)
  • University of Alabama at Birmingham (US)
Corresponding author
  • Sofroniew, Michael V
  • Khakh, Baljit S
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2014-03-30
Volume
17
Issue
5
Pages
694-703
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/nn.3691
PMC
PMC4064471
OpenAlex
W2129082075
Cited by
592
References
1
Citations by year
2026: 21 · 2025: 39 · 2024: 43 · 2023: 60 · 2022: 49 · 2021: 63 · 2020: 47 · 2019: 58 · 2018: 48 · 2017: 37 · 2016: 60 · 2015: 45 · 2014: 22
FWCI
25.00
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institute of Mental Health (MH104069, DP1MH104069)
  • National Institute of Neurological Disorders and Stroke (NS060677, R01NS060677, R01NS075062)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Keywords
Huntington's disease, Kir4.1, astrocytes, medium spiny neurons, neuronal excitability, potassium homeostasis, extracellular potassium, striatum, R6/2 mice, mutant huntingtin, astrocyte activation, viral gene delivery, motor function, therapeutic target
MeSH terms
Huntingtin Protein, Kcnj10 Channel, Age Factors, Animals, Astrocytes, Corpus Striatum, Disease Models, Animal, Humans, Huntington Disease, Locomotion, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Survival Analysis, Trinucleotide Repeats, Hindlimb Suspension, Potassium Channels, Inwardly Rectifying, Green Fluorescent Proteins, Mice, HEK293 Cells, In Vitro Techniques

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