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

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

Author information

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].

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.

Comment in

PMID:
24686787
PMCID:
PMC4064471
DOI:
10.1038/nn.3691
[Indexed for MEDLINE]
Free PMC Article

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