Studies of neurodegenerative disease often overlook astrocytes, the glial cells that surround and nurture neurons. For some years, evidence has grown to suggest they play an important role. Now, in the March 30 Nature Neuroscience, researchers led by Michael Sofroniew and Baljit Khakh at the University of California, Los Angeles, report that astrocytes make neurons sick in mouse models of Huntington’s disease. Striatal astrocytes containing mutant huntingtin protein made less of a crucial potassium channel, and therefore could not effectively mop up the ion, the authors found. This resulted in high extracellular potassium levels, which in turn rendered striatal neurons hyperexcitable. In mice, boosting expression of the potassium channel ameliorated some HD-like phenotypes such as motor deficits and premature death, suggesting that this mechanism accounts for at least some of the symptoms of Huntington’s. 

 “I think the paper highlights the potential for targeting astrocytes, not only in Huntington’s, but in other neurodegenerative disorders as well,” Donna Wilcock at the University of Kentucky, Lexington, wrote to Alzforum (see full comment below). She was not involved in the work, but had previously reported that astrocytes lose potassium channels in Alzheimer’s disease (see Feb 2009 news story). Intriguingly, faulty potassium channels underlie motor deficits in models of ataxia, as well (see May 2011 news story), implying that this could be a shared mechanism of neurodegeneration.

Human astrocyte culture stained for GFAP.


In Huntington’s disease, medium spiny neurons in the striatum die, causing severe movement problems. Several previous studies had implicated astrocytes in the pathology of the disease. For example, wild-type medium spiny neurons die when cultured with astrocytes containing mutant huntingtin (mHTT), and mice that express mHTT only in astrocytes have motor defects and die prematurely. In part, this may be because in both mice and people, mHTT astrocytes produce less of a glutamate transporter, leading to high extracellular glutamate that poisons neurons (see Shin et al., 2005Bradford et al., 2009Faideau et al., 2010). 

To further investigate the role of astrocytes, joint first authors Xiaoping Tong and Yan Ao characterized these cells in two mouse models of HD. One model, R6/2, develops aggressive disease, while the other, Q175, progresses slowly. Tong and colleagues found that astrocytes from either model became abnormally depolarized as the animals aged, and traced this effect to a lack of the Kir4.1 potassium channel in astrocytes with mHTT aggregates. The authors then focused on R6/2 mice, finding that extracellular potassium levels in these animals were doubled (3 mM instead of 1.5 mM). In striatal slices from wild-type mice, 3 mM of potassium was sufficient to make medium spiny neurons hyperexcitable to a similar degree as they are in HD mouse brains.

The authors then restored astrocyte Kir4.1 expression by virally delivering the protein into R6/2 mouse striatum. This procedure normalized extracellular potassium levels and the electrical properties of astrocytes. In medium spiny neurons, the membrane potential returned to normal and excitability improved somewhat. At the behavioral level, treated mice walked better, but did not improve in their ability to balance on a rotarod or grab with their paws. R6/2 mice normally die at around 98 days old; treated animals lived about 18 days longer.

The partial behavioral improvements reflect the fact that high potassium represents but one of many things that go awry in HD brains, Khakh said. In future collaborative studies, the authors plan to test a larger number of behaviors in multiple HD models to figure out which symptoms of disease this mechanism causes. 

In the minds of other scientists, the data raise new questions. For example, what makes Kir4.1 levels fall? The authors saw no change in mRNA transcripts and no direct interaction between mHTT and Kir4.1. Khakh suggested that mHTT might affect the trafficking or regulation of Kir4.1. Khakh and Ben Barres at Stanford University, Stanford, California, noted that astrocyte Kir4.1 expression has been shown to depend upon a signal from neurons (see Barres et al., 1990). This cellular communication might fail in HD, Barres suggested. Another puzzle is what makes striatal astrocytes selectively vulnerable to this phenomenon. Hippocampal astrocytes, for example, also express Kir4.1, but were not depolarized in the HD models studied here.

Commentators agreed that understanding how and at what stage Kir4.1 becomes dysfunctional will be crucial for determining whether it could be targeted therapeutically. Gilles Bonvento at INSERM-CEA, Fontenay-aux-Roses, France, noted that if the loss of Kir4.1 represents a late effect of disease, then it is unlikely to make a good target. It will also be important to show whether potassium levels are disrupted in human HD brains, Bonvento said. George Rebec at Indiana University, Bloomington, wondered how extracellular potassium might affect glutamate, which is known to be excitotoxic. “[The new finding] is very significant because it adds another dimension to growing evidence that astrocyte dysfunction plays a critical role in HD,” Rebec wrote to Alzforum.—Madolyn Bowman Rogers.


  1. These findings are very significant and add to the growing body of literature suggesting that astrocytes play a pivotal role in neurodegenerative disorders, as well as simply being bystanders in the disease process.

    It is too early to suggest that this could be a target for HD therapies. Also, more studies should be done looking at other components of the astrocytic end-feet, such as aquaporin 4 or the other potassium channel, the BK (Maxi-K) channel, also thought to be involved in potassium buffering by astrocytes (Puwarawuttipanit et al., 2006; Amiry-Moghaddam et al., 2003; Girouard et al., 2010). However, I think the paper highlights the potential for targeting astrocytes, not only in HD, but other neurodegenerative disorders.

    With respect to our work in Alzheimer’s disease, this adds further support to our hypothesis that potassium buffering is disrupted in AD. As we have shown previously, the loss of Kir4.1 in AD and in transgenic mouse models is associated with the presence of CAA (Wilcock et al., 2009). We are continuing to work on this, in particular now in our vascular dementia models. It is very encouraging to see similar findings in another neurodegenerative disease model. It is especially exciting to see the authors explore the functional consequences of the Kir4.1 loss on potassium buffering and neuronal excitability.


    . Differential effect of alpha-syntrophin knockout on aquaporin-4 and Kir4.1 expression in retinal macroglial cells in mice. Neuroscience. 2006;137(1):165-75. Epub 2005 Oct 28 PubMed.

    . Delayed K+ clearance associated with aquaporin-4 mislocalization: phenotypic defects in brains of alpha-syntrophin-null mice. Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13615-20. Epub 2003 Nov 3 PubMed.

    . Astrocytic endfoot Ca2+ and BK channels determine both arteriolar dilation and constriction. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3811-6. Epub 2010 Feb 2 PubMed.

    . Vascular amyloid alters astrocytic water and potassium channels in mouse models and humans with Alzheimer's disease. Neuroscience. 2009 Mar 31;159(3):1055-69. Epub 2009 Jan 19 PubMed.

    View all comments by Donna M. Wilcock
  2. Comment posted by the editors on behalf of Xiao-Jiang Li, Distinguished Professor of Human Genetics, Emory University School of Medicine: I read this paper and found it an interesting work. The new finding is that improving glial function can alleviate motor deficits in HD mice. The authors provided compelling evidence for the dysfunction of Kir4.1 ion channel in astrocytes in HD mice. This fits with previous findings that mutant huntingtin is expressed in astrocytes to affect astrocyte and neuronal function. Most previous studies focused on the effect of mutant huntingtin on neuronal cells and tried to find ways to improve neuronal function. This current study, however, shows that improving Kir4.1 expression in astrocytes could also reduce huntingtin toxicity on striatal neuronal cells and some motor deficit, suggesting that improving astrocyte function can be an alternative therapeutic approach. However, the study also opens more questions to address. The mechanism for mutant huntingtin to reduce the level of Kir4.1 remains to be investigated. The relative contribution of mutant huntingtin in astrocytes to the striatal neuronal dysfunction and HD symptoms remains unknown, as only some motor dysfunction is improved by overexpression of Kir4.1 in astrocytes. Despite these, the study demonstrated for the first time that improving astrocytic function can be beneficial to treating HD mouse phenotypes.

    View all comments by Alzforum Editors

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News Citations

  1. Sleep On It—Astrocytes May Play Key Roles in PD, AD
  2. In a Fish With Ataxia, Ions Can’t Surf Its Channels

Paper Citations

  1. . Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity. J Cell Biol. 2005 Dec 19;171(6):1001-12. PubMed.
  2. . Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms. Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22480-5. PubMed.
  3. . In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington's disease subjects. Hum Mol Genet. 2010 Aug 1;19(15):3053-67. Epub 2010 May 21 PubMed.
  4. . Ion channel expression by white matter glia: the type-1 astrocyte. Neuron. 1990 Oct;5(4):527-44. PubMed.

Further Reading

Primary Papers

  1. . Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington's disease model mice. Nat Neurosci. 2014 May;17(5):694-703. Epub 2014 Mar 30 PubMed.