Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington's disease model mice

Tong, Xiaoping; Ao, Yan; Faas, Guido C.; Nwaobi, Sinifunanya E.; Xu, Jimmy P.; Haustein, Martin D.; Anderson, Mark; Módy, István; Olsen, Michelle L.; Sofroniew, Michael V.; Khakh, Baljit S.

doi:10.1038/nn.3691

Cited by 517 publications

(536 citation statements)

References 49 publications

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“…Reduced activity of the astrocyte potassium channel K ir 4.1 in HD mice was associated with increased extracellular potassium concentrations and a depolarized MSN membrane potential [69]. These data suggest that astrocytes might represent an important target for normalizing MSN function, in addition to the MSNs themselves.…”

Section: Msn Dysfunction In Hd Modelsmentioning

confidence: 80%

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

Chopra

Shakkottai

2014

Neurotherapeutics

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Polyglutamine diseases are a class of neurodegenerative diseases that share an expansion of a glutamineencoding CAG tract in the respective disease genes as a central hallmark. In all of these diseases there is progressive degeneration in a select subset of neurons, and the mechanisms behind this degeneration remain unclear. Emerging evidence from animal models of disease has identified abnormalities in synaptic signaling and intrinsic excitability in affected neurons, which coincide with the onset of symptoms and precede apparent neuropathology. The appearance of these early changes suggests that altered neuronal activity might be an important component of network dysfunction and that these alterations in network physiology could contribute to symptoms of disease. Here we review abnormalities in neuronal function that have been identified in both animal models and patients, and highlight ways in which these changes in neuronal activity may contribute to disease symptoms. We then review the literature supporting an emerging role for abnormalities in neuronal activity as a driver of neurodegeneration. Finally, we identify common themes that emerge from studies of neuronal dysfunction in polyglutamine disease.

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Section: Msn Dysfunction In Hd Modelsmentioning

confidence: 80%

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

Chopra

Shakkottai

2014

Neurotherapeutics

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“…The control sample (GCM wt scrambled) shown in b and in Figure 3b is the same. See Supplementary Figure 9 for full-length pictures of the blots shown in b HD, 37 highlighting that some electrophysiological features of striatal dysfunction in HD can be secondary to glial disturbances. Here, we demonstrate that HD astrocytes affect neuronal function through their reduced synthesis and secretion of cholesterol bound to apoE lipoproteins.…”

Section: Discussionmentioning

confidence: 99%

Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington’s disease

et al. 2014

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In the adult brain, neurons require local cholesterol production, which is supplied by astrocytes through apoE-containing lipoproteins. In Huntington's disease (HD), such cholesterol biosynthesis in the brain is severely reduced. Here we show that this defect, occurring in astrocytes, is detrimental for HD neurons. Astrocytes bearing the huntingtin protein containing increasing CAG repeats secreted less apoE-lipoprotein-bound cholesterol in the medium. Conditioned media from HD astrocytes and lipoprotein-depleted conditioned media from wild-type (wt) astrocytes were equally detrimental in a neurite outgrowth assay and did not support synaptic activity in HD neurons, compared with conditions of cholesterol supplementation or conditioned media from wt astrocytes. Molecular perturbation of cholesterol biosynthesis and efflux in astrocytes caused similarly altered astrocyteneuron cross talk, whereas enhancement of glial SREBP2 and ABCA1 function reversed the aspects of neuronal dysfunction in HD. These findings indicate that astrocyte-mediated cholesterol homeostasis could be a potential therapeutic target to ameliorate neuronal dysfunction in HD. Huntington's disease (HD) is an adult-onset neurodegenerative disorder characterized by cell loss mainly in the striatum and cortex. Its pathophysiology is linked to an expanded CAG repeat in the IT-15 gene, which leads to an elongated polyQ tract in huntingtin (HTT) protein. No disease-modifying treatment is available for HD and novel pathophysiological insights and therapeutic strategies are needed. 1 Lipids are vital to brain health and function. Accordingly, the brain has a local source of cholesterol, 2 and a breakdown of cholesterol synthesis causes brain malformations and impaired cognitive function. 3,4 Cholesterol metabolism is disrupted in HD 5,6 as revealed by transcriptional, biochemical, and mass spectrometry analyses in HD rodent models. 7,8 This dysregulation is linked to a specific action of mutant HTT on sterol-regulatory-element-binding proteins (SREBPs) and on its target genes, whose reduced transcription leads to lower brain cholesterol levels. 7 In HD humans, brain cholesterol homeostasis is affected since pre-symptomatic stages, as determined by measurement of the brain-specific cholesterol catabolite 24-S-hydroxy-cholesterol (24OHC). 9,10 However, it remains unclear how reduced brain cholesterol would become pathological for HD neurons.In adulthood, astrocytes produce cholesterol, which is secreted as a complex with apolipoprotein (apo) E lipoproteins and delivered to neurons. 11,12 Mutant HTT is expressed in glial cells, 13,14 and transgenic mice overexpressing mutant HTT in astrocytes show age-dependent neurological symptoms. 15,16 Additionally, primary astrocytes overexpressing full-length human mutant HTT show reduced mRNA levels of cholesterol biosynthetic genes, along with impaired cellular production and secretion of apoE. 8 Here we employed molecular and cellular tools to test the impact of cholesterol perturbation between astrocytes and neur...

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“…Decreased expression of Kir4.1 K + channels leads to elevated striatal extracellular K + in vivo which can result in depolarization of neurons. Genetic restoration of Kir4.1 levels in striatal astrocytes returned extracellular K + and MSN excitability to normal, along with improvement of some motor functions in R6/2 mice (Tong et al, 2014). Recent work confirmed that the loss of astrocytic Kir4.1‐ and EAAT2‐mediated homeostatic functions in R6/2 mice compromises glutamate handling and Ca 2+ signaling, contributing to MSNs pathology in the striatum (Jiang, Diaz‐Castro, Looger, & Khakh, 2016).…”

Section: Astrocytes In the Diseased Brain Are Central To Neuropathologymentioning

confidence: 99%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

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Astrocytes are key homeostatic cells of the central nervous system. They cooperate with neurons at several levels, including ion and water homeostasis, chemical signal transmission, blood flow regulation, immune and oxidative stress defense, supply of metabolites and neurogenesis. Astroglia is also important for viability and maturation of stem‐cell derived neurons. Neurons critically depend on intrinsic protective and supportive properties of astrocytes. Conversely, all forms of pathogenic stimuli which disturb astrocytic functions compromise neuronal functionality and viability. Support of neuroprotective functions of astrocytes is thus an important strategy for enhancing neuronal survival and improving outcomes in disease states. In this review, we first briefly examine how astrocytic dysfunction contributes to major neurological disorders, which are traditionally associated with malfunctioning of processes residing in neurons. Possible molecular entities within astrocytes that could underpin the cause, initiation and/or progression of various disorders are outlined. In the second section, we explore opportunities enhancing neuroprotective function of astroglia. We consider targeting astrocyte‐specific molecular pathways which are involved in neuroprotection or could be expected to have a therapeutic value. Examples of those are oxidative stress defense mechanisms, glutamate uptake, purinergic signaling, water and ion homeostasis, connexin gap junctions, neurotrophic factors and the Nrf2‐ARE pathway. We propose that enhancing the neuroprotective capacity of astrocytes is a viable strategy for improving brain resilience and developing new therapeutic approaches.

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Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington's disease model mice

Cited by 517 publications

References 49 publications

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington’s disease

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

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