Corticostriatal network dysfunction in Huntington's disease: Deficits in neural processing, glutamate transport, and ascorbate release

Rebec, George V.

doi:10.1111/cns.12828

Cited by 29 publications

(25 citation statements)

References 112 publications

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“…Disconnection from cortical afferents likely plays a major role in the subsequent dysfunction of the downstream striatal circuits. The breakdown of corticostriatal communication in HD has been extensively studied, and for detailed information the reader is referred to several excellent reviews available on this topic (Miller and Bezprozvanny, 2010;Raymond et al, 2011;Estrada-Sánchez and Rebec, 2013;Plotkin and Surmeier, 2015;Bunner and Rebec, 2016;Rebec, 2018). The conclusion that emerged from electrophysiological studies in slices as well as in vivo in multiple HD mouse models is that alterations in corticostriatal connections occur in two phases, with increased glutamate release and SPN hyperexcitation at the presymptomatic stage, followed by SPN silencing at the symptomatic stage (Figure 3) (Klapstein et al, 2001;Cepeda et al, 2003;Rebec et al, 2006;Joshi et al, 2009;André et al, 2011b;Miller et al, 2011;Raymond et al, 2011;Indersmitten et al, 2015;Rothe et al, 2015).…”

Section: Corticostriatal Projectionmentioning

confidence: 99%

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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Section: Corticostriatal Projectionmentioning

confidence: 99%

Cortical and Striatal Circuits in Huntington’s Disease

Blumenstock

Dudanova

2020

Front. Neurosci.

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“…As in the striatum, cortical interneurons are largely spared from degeneration [127], although data from a mouse model suggest that interneuron-pyramidal interactions are required for pyramidal neuron dysfunction [35]. Evidence from HD mouse models exists suggesting that cortical alterations, involving mainly cortical layers II/III, may actually precede striatal pathology [128,129]. For example, there are dendritic alterations including a reduced number of spines in cortical pyramidal neurons in Hdh Q7/Q111 KI and R6/2 mice, prior to striatal structural changes [130,131].…”

Section: Aberrant Corticostriatal Communicationmentioning

confidence: 99%

Cell-Autonomous and Non-cell-Autonomous Pathogenic Mechanisms in Huntington's Disease: Insights from In Vitro and In Vivo Models

Creus-Muncunill

Ehrlich

2019

Neurotherapeutics

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Huntington's disease (HD) is an autosomal dominant disorder caused by an expansion in the trinucleotide CAG repeat in exon-1 in the huntingtin gene, located on chromosome 4. When the number of trinucleotide CAG exceeds 40 repeats, disease invariably is manifested, characterized by motor, cognitive, and psychiatric symptoms. The huntingtin (Htt) protein and its mutant form (mutant huntingtin, mHtt) are ubiquitously expressed but although multiple brain regions are affected, the most vulnerable brain region is the striatum. Striatal medium-sized spiny neurons (MSNs) preferentially degenerate, followed by the cortical pyramidal neurons located in layers V and VI. Proposed HD pathogenic mechanisms include, but are not restricted to, excitotoxicity, neurotrophic support deficits, collapse of the protein degradation mechanisms, mitochondrial dysfunction, transcriptional alterations, and disorders of myelin. Studies performed in cell type-specific and regionally selective HD mouse models implicate both MSN cell-autonomous properties and cell-cell interactions, particularly corticostriatal but also with non-neuronal cell types. Here, we review the intrinsic properties of MSNs that contribute to their selective vulnerability and in addition, we discuss how astrocytes, microglia, and oligodendrocytes, together with aberrant corticostriatal connectivity, contribute to HD pathophysiology. In addition, mHtt causes cell-autonomous dysfunction in cell types other than MSNs. These findings have implications in terms of therapeutic strategies aimed at preventing neuronal dysfunction and degeneration.

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“…Thus, deficiencies in DA release in this region may have a detrimental effect on motor control. However, we emphasize that abnormalities in other neurotransmitter systems, such as glutamate [17] , GABA [18] , and acetylcholine [19] may also contribute to the HD motor phenotype either directly or by influencing dopamine. For example, acetylcholine can exert a strong influence over dopamine release in the CPu [20] ; thus, it is conceivable that impaired acetylcholine levels, as has been found previously in R6/2 mice [19] would result in diminished dopamine release.…”

Section: Resultsmentioning

confidence: 99%

Regional Differences in Dopamine Release in the R6/2 Mouse Caudate Putamen

et al. 2018

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Huntington's disease (HD) is a fatal neurodegenerative disorder that is characterized by degeneration of the striatum. Here, fast-scan cyclic voltammetry at carbon-fiber microelectrodes was used to uncover regional differences in dopamine (DA) release in the caudate putamen of R6/2 and wild-type control mice. We found a decreasing ventral-to-dorsal gradient in DA release, evoked by a single electrical stimulus pulse, in aged R6/2 mice. Moreover, under more intense stimulation conditions (120 pulses), DA release was significantly attenuated in the dorsal, but not in the ventral caudate. Autoradiography measurements using [H]WIN 35,428 revealed that the overall density of DA transporter (DAT) protein molecules was significantly less in R6/2 mice compared to WT control mice; however, quadrants of the caudate putamen were not differentially altered in the R6/2 mice. These data collectively suggest that DA release in the dorsal caudate region is more vulnerable with age progression compared to the ventral region.

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Corticostriatal network dysfunction in Huntington's disease: Deficits in neural processing, glutamate transport, and ascorbate release

Cited by 29 publications

References 112 publications

Cortical and Striatal Circuits in Huntington’s Disease

Cortical and Striatal Circuits in Huntington’s Disease

Cell-Autonomous and Non-cell-Autonomous Pathogenic Mechanisms in Huntington's Disease: Insights from In Vitro and In Vivo Models

Regional Differences in Dopamine Release in the R6/2 Mouse Caudate Putamen

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