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.


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


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