Editors' ChoiceNeurodegeneration

Defective Astrocytes in Huntington’s

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Sci. Signal.  20 May 2014:
Vol. 7, Issue 326, pp. ec138
DOI: 10.1126/scisignal.2005494

Astrocytes are the most abundant cell type in the brain and provide structural, metabolic, and functional support for neurons, such as siphoning ions from the extracellular space. The accumulation of extracellular potassium depolarizes neurons and causes epileptic activity, a feature of some neurological diseases, including Huntington’s disease (HD). Tong et al. found that decreased abundance of a potassium channel in astrocytes contributed to neuronal dysfunction in mouse models of HD (see also Chan and Surmeier). HD is characterized by an initial asymptomatic phase and a symptomatic phase. The concentration of extracellular potassium was increased in the striatum of symptomatic HD mice compared with that in wild-type mice. Kir4.1 channels are the predominant potassium channel in astrocytes and more efficiently take up extracellular potassium than release it, enabling neighboring neurons to repolarize after excitation and return to a resting membrane potential. Channel-specific blockers revealed that the amplitude of Kir4.1 channel currents was lower in astrocytes from symptomatic HD mice than those from wild-type mice. Kir4.1 abundance in striatal tissue of symptomatic HD mice was decreased at the protein but not transcriptional level compared with presymptomatic or wild-type mice and was inversely correlated with nuclear aggregation of mutant huntingtin protein. Striatal astrocytes in brain slices from symptomatic HD mice had increased resting membrane potential (that is, they were more depolarized) and decreased membrane conductance compared with those from either wild-type mice or presymptomatic HD mice. Medium spiny neurons in HD mice were also more depolarized than those in wild-type mice, a phenomenon that is also detected in medium spiny neurons in HD patients. Restoring Kir4.1 abundance specifically to striatal astrocytes decreased the extracellular potassium concentration and rescued the abnormal electrophysiological phenotypes in both astrocytes and medium spiny neurons in HD mice. The findings implicate defects in astrocytes in the pathogenesis of HD and suggest that therapeutically correcting Kir4.1 channel activity in astrocytes may restore neuronal function in HD patients.

X. Tong, Y. Ao, G. C. Faas, S. E. Nwaobi, J. Xu, M. D. Haustein, M. A. Anderson, I. Mody, M. L. Olsen, M. V. Sofroniew, B. S. Khakh, Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington’s disease model mice. Nat. Neurosci. 17, 694–703 (2014). [PubMed]

C. S. Chan, D. J. Surmeier, Astrocytes go awry in Huntington's disease. Nat. Neurosci. 17, 641–642 (2014). [PubMed]

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