Hyperactive striatal neurons in symptomatic Huntington R6/2 mice: Variations with behavioral state and repeated ascorbate treatment

Rebec, George V.; Conroy, Susan K.; Barton, Scott J.

doi:10.1016/j.neuroscience.2005.08.062

Cited by 80 publications

(88 citation statements)

References 48 publications

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“…A priori, our data do not appear to corroborate previously described elevated striatal activity in the similar R6/2 mice exploring in an open field (22,23). Along with the differences in transgenic lines and behavioral conditions used for recording, difference in disease advancement could account for the discrepancy.…”

Section: Discussioncontrasting

confidence: 99%

“…Along with the differences in transgenic lines and behavioral conditions used for recording, difference in disease advancement could account for the discrepancy. Although we are aware of no study in R6/1 mice, an in vitro intracellular recording study in R6/2 mice once again showed that their striatal MSNs were hyperexcitable at a presymptomatic age (6 wk), consistent with data from Rebec's group (22,23), and became hypoexcitable later at a symptomatic age (12 wk) (16). Another study of YAC128 transgenic mice also reported biphasic increase and subsequent decrease of synaptic transmission in the corticostriatal pathway with disease progression (24).…”

Section: Discussionsupporting

confidence: 78%

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Changes in striatal procedural memory coding correlate with learning deficits in a mouse model of Huntington disease

Cayzac

Delcasso

Paz

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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In hereditary neurodegenerative Huntington disease (HD), early cognitive impairments before motor deficits have been hypothesized to result from dysfunction in the striatum and cortex before degeneration. To test this hypothesis, we examined the firing properties of single cells and local field activity in the striatum and cortex of pre-motor-symptomatic R6/1 transgenic mice while they were engaged in a procedural learning task, the performance on which typically depends on the integrity of striatum and basal ganglia. Here, we report that a dramatically diminished recruitment of the vulnerable striatal projection cells, but not local interneurons, of R6/1 mice in coding for the task, compared with WT littermates, is associated with severe deficits in procedural learning. In addition, both the striatum and cortex in these mice showed a unique oscillation at high γ-frequency. These data provide crucial information on the in vivo cellular processes in the corticostriatal pathway through which the HD mutation exerts its effects on cognitive abilities in early HD.single unit | local field potential | high γ-oscillation | operant learning | pre-motor-symptomatic R6/1 mice H untington disease (HD) is a progressive and inherited neurodegenerative disorder associated with selective degeneration of medium-sized spiny projection neurons in the striatum (1). Although the disease is well characterized by symptoms such as involuntary choreiform movements, dystonias, and rigidity, these motor symptoms have been found to be preceded by personality, mood, and cognitive disturbances (2). Some postmortem studies have also shown only limited signs of pathologic processes or cell loss in the brain despite substantial clinical evidence of HD (3), suggesting that neuronal-and, more precisely, synapticdysfunction, rather than cell death, may predominantly underlie early behavioral manifestations of the HD mutation.Studies of the effects of the mutant HD gene in several transgenic mouse models, including the R6 lines, have indeed shown changes in the membrane properties, biochemistry, and morphology of fragile striatal cells (4, 5), suggesting compromised functional integrity. They have also shown early and progressive alterations in synaptic plasticity in the corticostriatal pathway (6). These changes have been hypothesized to underlie early cognitive and behavioral deficits in transgenic mice (and patients with HD) by altering striatal information processing and transfer within basal ganglia loops.To verify this hypothesis, we recorded single-unit activity and local field potentials (LFPs) in the dorsal striatum and cortex, whereas behaviorally naive pre-motor-symptomatic R6/1 mice (7) (14-18 wk old) and age-matched WT littermates acquired an association between a nose-poke (NP) action and reward through operant learning. This procedural learning of an action-reward association is known to critically involve the striatum, a crucial site for the integration of the sensorimotor, limbic, and cognitive information required for the selecti...

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 78%

Changes in striatal procedural memory coding correlate with learning deficits in a mouse model of Huntington disease

Cayzac

Delcasso

Paz

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…According with a role of ascorbate in the behavioral phenotype of R6/2 mice, this treatment significantly reduced stereotypical hind limb grooming and increased the performance in a plus-maze test, although no effect was observed on the overall locomotion (evaluated in an open field apparatus) (Rebec et al, 2003). Furthermore, restoring the levels of striatal extracellular ascorbate to wild-type levels was enough to decrease striatal impulse activity (which was shown to be significantly elevated in these animals), suggesting a role for ascorbate in normalizing neuronal function in the striatum of R6/2 mice (Rebec et al, 2006).…”

Section: Antioxidantsmentioning

confidence: 88%

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

Gil

Rego

2009

Brain Research Reviews

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Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an expanded CAG repeat in the HD gene that results in cortical and striatal degeneration, and mutant huntingtin aggregation. Current treatments are unsatisfactory. R6 transgenic mice replicate many features of the human condition, show early onset of symptoms and fast disease progression, being one of the most used models for therapy screening. Here we review the therapies that have been tested in these mice: environmental enrichment, inhibition of histone deacetylation and methylation, inhibition of misfolding and oligomerization, transglutaminase inhibition, rescue of metabolic impairment, amelioration of the diabetic phenotype, use of antioxidants, inhibition of excitotoxicity, caspase inhibition, transplantation, genetic manipulations, and restoration of neurogenesis. Although many of these treatments were beneficial in R6 mice, they may not be as effective in HD patients, and thus the search for a combination of therapies that will rescue the human condition continues.

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“…gamma-aminobutyric acid-ergic interneuron populations within the striatum also show abnormalities at this time, with MSNs from the R6/2 model demonstrating increases in the frequency of spontaneous inhibitory postsynaptic currents (IPSCs) that appear to originate from these interneuron populations rather than the MSNs themselves [60,61]. Importantly, these changes have consequences for striatal network function, including a reduction in correlated firing of MSNs [62] and the emergence of glutamate-dependent MSN hyperactivity [63]. Taken together, these data suggest that the development of early motor symptoms associated with striatal dysfunction might reflect aberrant signaling through corticostriatal and intrastriatal inputs across multiple transmitter systems that influence MSN activity.…”

Section: Msn Dysfunction In Hd Modelsmentioning

confidence: 99%

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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Hyperactive striatal neurons in symptomatic Huntington R6/2 mice: Variations with behavioral state and repeated ascorbate treatment

Cited by 80 publications

References 48 publications

Changes in striatal procedural memory coding correlate with learning deficits in a mouse model of Huntington disease

Changes in striatal procedural memory coding correlate with learning deficits in a mouse model of Huntington disease

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

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

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