. 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.

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  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.

    References:

    . 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. PubMed.

  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.

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