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

Xiaoping Tong; Yan Ao; Guido C Faas; Sinifunanya E Nwaobi; Ji Xu; Martin D Haustein; Mark A Anderson; Istvan Mody; Michelle L Olsen; Michael V Sofroniew; Baljit S Khakh

doi:10.1038/nn.3691

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

Nat Neurosci. 2014 May;17(5):694-703. doi: 10.1038/nn.3691. Epub 2014 Mar 30.

Authors

Affiliations

¹ 1] Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [2].
² 1] Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [2].
³ Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
⁴ Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁵ Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
⁶ Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
⁷ 1] Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [2] Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
⁸ 1] Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [2] Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA. [3].

PMID: 24686787
PMCID: PMC4064471
DOI: 10.1038/nn.3691

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Age Factors
Animals
Astrocytes / metabolism*
Corpus Striatum / physiopathology
Disease Models, Animal
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
HEK293 Cells
Hindlimb Suspension / physiology
Humans
Huntingtin Protein
Huntington Disease / genetics
Huntington Disease / mortality
Huntington Disease / pathology*
Huntington Disease / physiopathology
In Vitro Techniques
Locomotion / genetics
Mice
Mice, Inbred C57BL
Mice, Transgenic
Nerve Tissue Proteins / genetics
Neurons / metabolism
Neurons / pathology*
Nuclear Proteins / genetics
Potassium Channels, Inwardly Rectifying / deficiency*
Potassium Channels, Inwardly Rectifying / genetics
Survival Analysis
Trinucleotide Repeats / genetics

Substances

Htt protein, mouse
Huntingtin Protein
Kcnj10 (channel)
Nerve Tissue Proteins
Nuclear Proteins
Potassium Channels, Inwardly Rectifying
Green Fluorescent Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding