Treadmill exercise delays the onset of non-motor behaviors and striatal pathology in the CAG140 knock-in mouse model of Huntington's disease

Stefanko, Daniel P.; Shah, Vivek; Yamasaki, W.K.; Petzinger, Giselle M.; Jakowec, Michael W.

doi:10.1016/j.nbd.2017.05.004

Cited by 23 publications

(14 citation statements)

References 56 publications

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“…In heterozygous Q140s, mutant HTT inclusions are found as early as 2 months of age (Menalled et al., ). Similar expression patterns were found in Q150 MSNs (Stefanko, Shah, Yamasaki, Petzinger, & Jakowec, ). Interestingly, for the Q150 line, the striatum seems to be particularly affected, displaying a higher number of nuclear aggregations and dense inclusions compared to cortical areas at 6 and 12 months.…”

Section: Cellular and Molecular Changessupporting

confidence: 74%

“…Similar to full‐length mouse models, KI models display a late‐onset motor phenotype directly related to the number of CAG repeats. For example, whereas the Q111 mouse shows few, if any, motor alterations (Menalled et al., ), homozygous Q140 mice display mild motor abnormalities in parameters such as distance in running wheel assessment at 3.5 months of age, but no changes are observed in latency to fall in rotarod or stride length (Stefanko et al., ), whereas Q150 mice show reduced latency to fall in rotarod at 10 months of age and reduced locomotor activity at 17, but reduced grip strength was found much earlier at 3 months (Rattray et al., ). Motor phenotype onset is more evident in Q175 mice: altered coordination in rotarod occurs at 6 to 7 months in both heterozygous and homozygous animals (Menalled et al., ; Smith et al., ; Peng et al., 2014).…”

Section: Behavioral Comparisonsmentioning

confidence: 99%

“…Few studies have been conducted in KI mouse models addressing depression‐like or anxiety‐like behavior. Q111 mice showed signs of such behavior at 3 to 4 months of age (Orvoen, Pla, Gardier, Saudou, & David, ; Stefanko et al., ) along with altered sensory gating as measured by the startle response at 12 to 13 months (Bragg et al., ; Menalled et al., ). In Q150 mice, deficits in PPI occurred at 6 months of age (Brooks et al., ).…”

Section: Behavioral Comparisonsmentioning

confidence: 99%

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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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Section: Cellular and Molecular Changessupporting

confidence: 74%

Section: Behavioral Comparisonsmentioning

confidence: 99%

Section: Behavioral Comparisonsmentioning

confidence: 99%

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

Rangel‐Barajas

Rebec

2018

CP Neuroscience

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“…For example, Q140 mice form mutant huntingtin aggregates in striatum as early as 2 months of age, with mice clearly symptomatic by 6 months of age. For these mice, Stefanko et al showed by Western blot that at 4 and 6 months of age, striatal D1 receptors are normal in abundance, but D2 receptors are reduced by 15% and 20%, respectively. Similar results are seen in heterozygous Q175 knock‐in mice, with our studies showing significant reduction in ENK message in striatum by 6 months of age but no SP reduction .…”

Section: Striatal Neuron Output Abnormalities In Hdmentioning

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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“…In R6/1 mice, sustained wheel running was shown to improve gait and motor coordination, as well as reduce striatal neuron loss [20]. More recent work with the longer life-span CAG140 mouse model demonstrated that 6 months of treadmill training resulted in increased striatal dopamine D2 receptor expression and dopamine neurotransmitter levels, reduction in HTT aggregate formation, as well as improved behavioural and cognitive symptoms [21]. These pre-clinical findings have set the stage for several clinical feasibility studies in people with early and moderate HD [22][23][24][25], as well as in several multi-disciplinary rehabilitation trials [26][27][28][29][30].…”

Section: Commentsmentioning

confidence: 99%