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Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntingtons disease model mice
Xiaoping Tong1,5, Yan Ao2,5, Guido C Faas3, Sinifunanya E Nwaobi4, Ji Xu1, Martin D Haustein1, Mark A Anderson2, Istvan Mody1,3, Michelle L Olsen4, Michael V Sofroniew2,6 & Baljit S Khakh1,2,6
Huntingtons 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.
npg 201 4 Nature America, Inc. All rights reserved.
Astrocytes contribute to the function of neurons and the brain13.
There is also growing appreciation that astrocytes contribute to neurological and psychiatric diseases2,46. HD is an autosomal dominant disorder characterized by progressive motor, cognitive and psychiatric disturbances associated with neuronal dysfunction and atrophy of the striatum and other brain regions. HD is caused by an expanded chain of polyglutamines localized to the Nterminal region of the huntingtin protein (HTT) that cause intracellular accumulation and aggregation of mutant HTT (mHTT)7. The physiological role of HTT and the mechanisms that produce the disease are largely unknown, although intense effort has focused on the study of the effects of mHTT expression on neuronal function, particularly in the striatum8. Recent studies have suggested that astrocytes may also be involved in HD. Brains from HD patients and from mouse models of HD show accumulation of mHTT in striatal astrocytes9,10. Selective expression of mHTT only in astrocytes leads to cell death of striatal neurons9, reduced glutamate transporter expression10 and agedependent broadly HDlike pathology11. However, these studies do not prove that astrocyte physiology is altered...