Integrative Characterization of the R6/2 Mouse Model of Huntington’s Disease Reveals Dysfunctional Astrocyte Metabolism

Skotte, Niels H.; Andersen, Jens V.; Santos, Alberto; Aldana, Blanca I.; Willert, Cecilie Wennemoes; Nørremølle, Anne; Nielsen, Michael L.

doi:10.1016/j.celrep.2018.04.052

Cited by 85 publications

(86 citation statements)

References 76 publications

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“…Our proteomic analyses demonstrated a major downregulation of synaptic proteins in R6/2 mice. In addition to confirming reductions in synaptic proteins shown at advanced disease stages in HD mice and human brain samples Smith et al, 2007;Skotte et al, 2018), our dataset reveals a broad downregulation of synaptic components that occurs already before disease onset. Surprisingly, the majority of synaptic proteins that were downregulated in the soluble fraction were not altered in the insoluble material at 8 weeks of age, arguing against sequestration as a major mechanism of synaptic protein depletion at this disease stage (Murmu et al, 2013;Kim et al, 2016;Hosp et al, 2017).…”

Section: Discussionsupporting

confidence: 74%

Cortical circuit alterations precede disease onset in Huntington’s disease mice

Neuner

Schulz-Trieglaff

Gutiérrez-Ángel

et al. 2018

Preprint

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Huntington’s disease (HD) is a devastating hereditary movement disorder, characterized by degeneration of neurons in the striatum and cortex. Studies in human patients and mouse HD models suggest that disturbances of neuronal function in the neocortex play an important role in the disease onset and progression. However, the precise nature and time course of cortical alterations in HD have remained elusive. Here, we use chronic in vivo two-photon calcium imaging to monitor the activity of single neurons in layer 2/3 of the primary motor cortex in awake, behaving R6/2 transgenic HD mice and wildtype littermates. R6/2 mice show age-dependent changes in neuronal activity with a clear increase in activity at the age of 8.5 weeks, preceding the onset of motor and neurological symptoms. Furthermore, quantitative proteomics demonstrate a pronounced downregulation of synaptic proteins in the cortex, and histological analyses in R6/2 mice and HD patient samples reveal reduced inputs from parvalbumin-positive interneurons onto layer 2/3 pyramidal cells. Thus, our study provides a time-resolved description as well as mechanistic details of cortical circuit dysfunction in HD.Significance statementFuntional alterations in the cortex are believed to play an important role in the pathogenesis of Huntington’s disease (HD). However, studies monitoring cortical activity in HD models in vivo at a single-cell resultion are still lacking. We have used chronic two-photon imaging to investigate changes in the activity of single neurons in the primary motor cortex of awake presymptomatic HD mice. We show that neuronal activity increases before the mice develop disease symptoms. Our histological analyses in mice and in human HD autopsy cases furthermore demonstrate a loss inhibitory synaptic terminals from parvalbimun-positive interneurons, revealing a potential mechanism of cortical circuit impairment in HD.

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Section: Discussionsupporting

confidence: 74%

Cortical circuit alterations precede disease onset in Huntington’s disease mice

Neuner

Schulz-Trieglaff

Gutiérrez-Ángel

et al. 2018

Preprint

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“…In particular, there was a downregulation of transcripts involved in the postsynaptic scaffold, neurotransmitter signaling, Ca 2+ signaling, long-term synaptic plasticity, as well as reduced transcription of neuronal activity-regulated genes (Langfelder et al, 2016;HD iPSC Consortium, 2017;Veldman and Yang, 2018;Victor et al, 2018). Importantly, these changes also hold true at the proteomic level (Langfelder et al, 2016;Hosp et al, 2017;Skotte et al, 2018). Quantitative mass spectrometry analysis in R6/2 mice demonstrated a progressive decline of both excitatory and inhibitory synaptic proteins (Burgold et al, 2019), in line with morphological and functional defects described for both types of synapses.…”

Section: Insights From Systems Biology Studiesmentioning

confidence: 96%

Cortical and Striatal Circuits in Huntington’s Disease

Blumenstock

Dudanova

2020

Front. Neurosci.

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Huntington's disease (HD) is a hereditary neurodegenerative disorder that typically manifests in midlife with motor, cognitive, and/or psychiatric symptoms. The disease is caused by a CAG triplet expansion in exon 1 of the huntingtin gene and leads to a severe neurodegeneration in the striatum and cortex. Classical electrophysiological studies in genetic HD mouse models provided important insights into the disbalance of excitatory, inhibitory and neuromodulatory inputs, as well as progressive disconnection between the cortex and striatum. However, the involvement of local cortical and striatal microcircuits still remains largely unexplored. Here we review the progress in understanding HD-related impairments in the cortical and basal ganglia circuits, and outline new opportunities that have opened with the development of modern circuit analysis methods. In particular, in vivo imaging studies in mouse HD models have demonstrated early structural and functional disturbances within the cortical network, and optogenetic manipulations of striatal cell types have started uncovering the causal roles of certain neuronal populations in disease pathogenesis. In addition, the important contribution of astrocytes to HD-related circuit defects has recently been recognized. In parallel, unbiased systems biology studies are providing insights into the possible molecular underpinnings of these functional defects at the level of synaptic signaling and neurotransmitter metabolism. With these approaches, we can now reach a deeper understanding of circuit-based HD mechanisms, which will be crucial for the development of effective and targeted therapeutic strategies.

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“…HD is associated with degeneration and loss of neurons in the striatum causing incessant involuntary movements and motor impairments [97]. Using system-wide analysis of the spatial proteome combined with mass spectrometric analysis, we have recently identified alterations in key proteins related to brain energy metabolism, particularly, glia metabolism in a mouse model of HD [15]. Striatal metabolism has been shown to be decreased prior to atrophy, and interestingly, disease progression is strongly correlated with glucose hypometabolism [98].…”

Section: Altered Brain Energy Metabolism In Neurodegenerative Disordersmentioning

confidence: 99%

“…Microglia and metabolism in AD "It is well recognized that neurodegenerative diseases are accompanied by deficits in brain energy metabolism [13][14][15]32]. Neuroinflammation, particularly derived from microglia activation, is also believed to contribute to such brain disorders.…”

Section: Microglial Metabolism and Neurodegenerative Disordersmentioning

confidence: 99%

“…Although little is known regarding the brain functions that are so energetically costly, it has been suggested that microglia surveillance and activation could place a considerable strain on the energy budget [12]. Interestingly, impairments in energy processing have been strongly linked to hampered brain function and neurodegeneration [13][14][15]. Specifically, decreased metabolism of glucose, the obligatory energy substrate in the brain, is widely accepted as an early hallmark in neurodegenerative diseases [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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Microglia-Specific Metabolic Changes in Neurodegeneration

Aldana

2019

Journal of Molecular Biology

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The high energetic demand of the brain deems this organ rather sensitive to changes in energy supply. Therefore, even minor alterations in energy metabolism may underlie detrimental disturbances in brain function, contributing to the generation and progression of neurodegenerative diseases. Considerable evidence supports the key role of deficits in cerebral energy metabolism, particularly hypometabolism of glucose and mitochondrial dysfunction, in the pathophysiology of brain disorders. Major breakthroughs in the field of bioenergetics and neurodegeneration have been achieved through the use of in vitro and in vivo models of disease as well as sophisticated neuroimaging techniques in patients, yet these have been mainly focused on neuron and astrocyte function. Remarkably, the subcellular metabolic mechanisms linked to neurodegeneration that operate in other crucial brain cell types such as microglia have remain obscured, although they are beginning to be unraveled. Microglia, the brain-resident immune sentinels, perform a diverse range of functions that require a high-energy expenditure, namely, their role in brain development, maintenance of the neural environment, response to injury and infection, and activation of repair programs. Interestingly, another key mechanism underlying several neurodegenerative diseases is neuroinflammation, which can be associated with chronic microglia activation. Considering that many brain disorders are accompanied by changes in brain energy metabolism and sustained inflammation, and that energy metabolism has a strong influence on the inflammatory responses of microglia, the emerging significance of microglial energy metabolism in neurodegeneration is highlighted in this review.

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Integrative Characterization of the R6/2 Mouse Model of Huntington’s Disease Reveals Dysfunctional Astrocyte Metabolism

Cited by 85 publications

References 76 publications

Cortical circuit alterations precede disease onset in Huntington’s disease mice

Cortical circuit alterations precede disease onset in Huntington’s disease mice

Cortical and Striatal Circuits in Huntington’s Disease

Microglia-Specific Metabolic Changes in Neurodegeneration

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