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., 2005; Bradford et al., 2009; Faideau 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.
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- Tong X, Ao Y, Faas GC, Nwaobi SE, Xu J, Haustein MD, Anderson MA, Mody I, Olsen ML, Sofroniew MV, Khakh BS. 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.