Alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of Huntington's disease

Sebastianutto, Irene; Cenci, M. Angela; Fieblinger, Tim

doi:10.1016/j.nbd.2017.05.011

Cited by 31 publications

(40 citation statements)

References 55 publications

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“…Thus, boosting the strength of striatopallidal synapses on prototypical GPe neurons could compensate for an impairment in corticostriatal excitation of iSPNs . The deficit in dendritic integration and excitability of HD iSPNs inferred from these studies has recently been challenged by Sebastianutto and colleagues . However, the dendritic imaging in this study was limited to proximal dendrites (<100 μm from the soma).…”

Section: Discussionmentioning

confidence: 87%

“…16,19 The deficit in dendritic integration and excitability of HD iSPNs inferred from these studies has recently been challenged by Sebastianutto and colleagues. 57 However, the dendritic imaging in this study was limited to proximal dendrites (<100 μm from the soma). Unpublished work by our group has corroborated these findings but has also shown that more distal dendritic regions, which make up most of the iSPN dendritic surface area and are governed by a distinctive set of ionic mechanisms, are indeed hypoexcitable in iSPNs from symptomatic Q175 het mice.…”

Section: Is the Alteration In Striatopallidal Synaptic Strength Compementioning

confidence: 99%

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Enhanced striatopallidal gamma‐aminobutyric acid (GABA)_A receptor transmission in mouse models of huntington's disease

et al. 2019

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Background Huntington's disease (HD) is caused by a CAG repeat expansion in the huntingtin gene. This mutation leads to progressive dysfunction that is largely attributable to dysfunction of the striatum. The earliest signs of striatal pathology in HD are found in indirect pathway gamma‐Aminobutyric acid (GABA)‐ergic spiny projection neurons that innervate the external segment of the globus pallidus (GPe). What is less clear is whether the synaptic coupling of spiny projection neurons with GPe neurons changes in HD. Objectives The principal goal of this study was to determine whether striatopallidal synaptic transmission was altered in 2 mouse models of HD. Methods Striatopallidal synaptic transmission was studied using electrophysiological and optogenetic approaches in ex vivo brain slices from 2 HD models: Q175 heterozygous (het) and R6/2 mice. Results Striatopallidal synaptic transmission increased in strength with the progression of behavioral deficits in Q175 and R6/2 mice. The alteration in synaptic transmission was evident in both prototypical and arkypallidal GPe neurons. This change did not appear attributable to an increase in the probability of GABA release but, rather, to an enhancement in the postsynaptic response to GABA released at synaptic sites. This alteration significantly increased the ability of striatopallidal axon terminals to pause ongoing GPe activity. Conclusions In 2 mouse models of HD, striatopallidal synaptic transmission increased in parallel with the progression of behavioral deficits. This adaptation could compensate in part for the concomitant deficit in the ability of corticostriatal signals to activate spiny projection neurons and pause GPe activity. © 2019 International Parkinson and Movement Disorder Society

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Section: Discussionmentioning

confidence: 87%

Section: Is the Alteration In Striatopallidal Synaptic Strength Compementioning

confidence: 99%

Enhanced striatopallidal gamma‐aminobutyric acid (GABA)_A receptor transmission in mouse models of huntington's disease

et al. 2019

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“…Note, however, as they did not examine dSPNs in this study, it is uncertain whether they do or do not show the enhanced excitability found in iSPNs. 123 Thus, while increased excitability and disrupted burst firing would interfere with striatal control of its target areas, it is uncertain whether the disruption differs between dSPNs and iSPNs and is a cause of any differential functional deficits in the direct and indirect striatal output pathways.…”

Section: Functional Implications Of Differential Vulnerability Of Smentioning

confidence: 99%

Disrupted striatal neuron inputs and outputs in Huntington's disease

Reiner

Deng

2018

CNS Neurosci Ther

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Huntington's disease (HD) is a hereditary progressive neurodegenerative disorder caused by a CAG repeat expansion in the gene coding for the protein huntingtin, resulting in a pathogenic expansion of the polyglutamine tract in the N-terminus of this protein. The HD pathology resulting from the mutation is most prominent in the striatal part of the basal ganglia, and progressive differential dysfunction and loss of striatal projection neurons and interneurons account for the progression of motor deficits seen in this disease. The present review summarizes current understanding regarding the progression in striatal neuron dysfunction and loss, based on studies both in human HD victims and in genetic mouse models of HD. We review evidence on early loss of inputs to striatum from cortex and thalamus, which may be the basis of the mild premanifest bradykinesia in HD, as well as on the subsequent loss of indirect pathway striatal projection neurons and their outputs to the external pallidal segment, which appears to be the basis of the chorea seen in early symptomatic HD. Later loss of direct pathway striatal projection neurons and their output to the internal pallidal segment account for the severe akinesia seen late in HD. Loss of parvalbuminergic striatal interneurons may contribute to the late dystonia and rigidity.

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“…Mutant HTT abnormally aggregates in the nucleus and cytoplasm, promoting cellular dysfunction, dystrophic neurites, neuronal atrophy, and neuronal death (Babcock & Ganetzky, ; DiFiglia et al., ; Sebastianutto, Cenci, & Fieblinger, ). The most vulnerable neurons are the medium‐sized spiny neurons (MSNs) of the striatum, the main input structure of the basal ganglia (Calabresi et al., ; DiFiglia et al., ; Sepers & Raymond, ), which receives glutamatergic projections from all cortical areas (Reiner, Hart, Lei, & Deng, ).…”

Section: Clinical Overview Of Huntington's Diseasementioning

confidence: 99%

“…In symptomatic R6/1 and R6/2 mice, the density of cortical dendritic fields decreases along the length of MSN spines (Klapstein et al., ; Laforet et al., ; Spires et al., ; Stack et al., ). In addition, alterations of striatal afferent morphology consistently precede motor onset (Samadi et al., ; Sebastianutto et al., ).…”

Section: Neuropathological Featuresmentioning

confidence: 99%

Overview of Huntington's Disease Models: Neuropathological, Molecular, and Behavioral Differences

Rangel‐Barajas

Rebec

2018

CP Neuroscience

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Transgenic mouse models of Huntington's disease (HD), a neurodegenerative condition caused by a single gene mutation, have been transformative in their ability to reveal the molecular processes and pathophysiological mechanisms underlying the HD behavioral phenotype. Three model categories have been generated depending on the genetic context in which the mutation is expressed: truncated, full-length, and knock-in. No single model, however, broadly replicates the behavioral symptoms and massive neuronal loss that occur in human patients. The disparity between model and patient requires careful consideration of what each model has to offer when testing potential treatments. Although the translation of animal data to the clinic has been limited, each model can make unique contributions toward an improved understanding of the neurobehavioral underpinnings of HD. Thus, conclusions based on data obtained from more than one model are likely to have the most success in the search for new treatment targets. © 2018 by John Wiley & Sons, Inc.

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Alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of Huntington's disease

Cited by 31 publications

References 55 publications

Enhanced striatopallidal gamma‐aminobutyric acid (GABA)_A receptor transmission in mouse models of huntington's disease

Enhanced striatopallidal gamma‐aminobutyric acid (GABA)_A receptor transmission in mouse models of huntington's disease

Disrupted striatal neuron inputs and outputs in Huntington's disease

Overview of Huntington's Disease Models: Neuropathological, Molecular, and Behavioral Differences

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Alterations of striatal indirect pathway neurons precede motor deficits in two mouse models of Huntington's disease

Cited by 31 publications

References 55 publications

Enhanced striatopallidal gamma‐aminobutyric acid (GABA)A receptor transmission in mouse models of huntington's disease

Enhanced striatopallidal gamma‐aminobutyric acid (GABA)A receptor transmission in mouse models of huntington's disease

Disrupted striatal neuron inputs and outputs in Huntington's disease

Overview of Huntington's Disease Models: Neuropathological, Molecular, and Behavioral Differences

Contact Info

Product

Resources

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Enhanced striatopallidal gamma‐aminobutyric acid (GABA)_A receptor transmission in mouse models of huntington's disease

Enhanced striatopallidal gamma‐aminobutyric acid (GABA)_A receptor transmission in mouse models of huntington's disease