HD Insights™

3 HD Insights, Vol. 13 Highly Cited HD Research H D I N S I G H T S Astrocytes in HD Copyright © Huntington Study Group 2016. All rights reserved. In this edition of HD Insights, we take a look at some of the most impactful HD research articles of 2014. We searched Thomson Reuters' "Web of Science" service in December 2015 and identified five papers as the most highly cited original research articles on HD published in 2014. Reviews and book chapters were excluded, as well as articles pertaining only tangentially to HD. We contacted the corresponding authors and requested articles on their work, and received the following responses. These pieces highlight several ongoing areas of exploration in clinical and basic science research in HD, and suggest new frontiers for clinical practice and potential therapeutic targets. By: Baljit S. Khakh, PhD and Michael V. Sofroniew, MD, PhD Understanding the mechanisms that lead to neurological and psychiatric disorders remains a major goal of neuroscience. Considerable advances have been made in understanding the roles of neurons in brain function and disease. In contrast, astrocytes, which represent about half the cells in the human brain, have been less thoroughly investigated. Recent studies show that astrocytes are essential for the normal activity of neural circuits, but the possibility that astrocyte dysfunction may contribute to, or perhaps even drive disease mechanisms, remains incompletely explored. 1 Broad analyses show that recent neuroscience drug development based on our improved understanding of neurons has resulted in many failures, suggesting that investigating astrocytes in diseases such as HD may be beneficial. 2 Evidence suggests that astrocytes may be involved in HD. Brains from HD patients and from mouse models of HD show accumulation of mutant huntingtin protein (mHTT) in striatal astrocytes, which contributes to age-dependent HD-like pathology (see Figure, part a). 3 However, it remains unknown whether and how astrocytes contribute to HD pathology or disease mechanisms. We therefore used HD mouse models R6/2 and Q175 to assess astrocyte contributions to HD pathophysiology. 4 We found that concomitant with the onset of HD symptoms, significantly more astrocytes had mHTT inclusions and significant reductions in important functional proteins (including the potassium channel Kir4.1) without major phenotypic changes associated with astrocyte reactivity. These findings suggest that mHTT is associated with early disruption of the expression of important astrocyte functional proteins that alters astrocyte function (see Figure, part b) without triggering astrogliosis. Congruent with other studies of mouse models and human HD, we found progressively increasing astrogliosis at later disease stages that exhibit overt neurodegeneration. Based on past studies, the loss of Kir4.1 currents in striatal astrocytes predicts reduced spatial K + buffering, which, in the simplest interpretation, would lead to higher ambient K + levels. We found that the extracellular K + concentration was doubled in R6/2 mice, prompting us to explore the impact of increased K + on the properties of striatal medium spiny neurons (MSNs). Figure: Striatal astrocytes from R6/2 HD-model mice display nuclear mHTT inclusions and lower membrane conductances. a. Representative immunofluorescence images showing that GFAP, S100, GS and Aldh1L1−labeled astrocytes (green) contain nuclear mHTT inclusions. Nuclei were labeled blue with DAPI, and mHTT is shown in white. b. Representative traces of whole-cell voltage-clamp recordings from striatal astrocytes from WT and R6/2 mice at P60. The current waveforms show the response to a step depolarization, revealing clear differences in membrane conductance between WT and R6/2 astrocytes. Original Article: Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington's disease model mice (cited 45 times as of 2/8/2016)

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