GABAergic circuits in the basal ganglia and movement disorders

Galván, Adriana; Wichmann, Thomas

doi:10.1016/s0079-6123(06)60017-4

Cited by 61 publications

(49 citation statements)

References 251 publications

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“…3B–G). We measured parameters that would capture both mobility and immobility because these different aspects of motor function are believed to be controlled by distinct pathways within the basal ganglia and may be differentially affected by dopamine depletion (Albin, Young et al 1989, DeLong 1990, Graybiel, Aosaki et al 1994, Schwarting and Huston 1996, Schwarting and Huston 1996, Day, Wang et al 2006, Mallet, Ballion et al 2006, Galvan and Wichmann 2007, Kreitzer and Malenka 2007, Gittis, Hang et al 2011). Gradually depleted mice were grouped into five groups, based on percent dopamine remaining (89.8 ± 2.4%, n = 10; 73.9 ± 1.8%, n = 9; 51.8 ± 1.3%, n = 22; 30.1 ± 1.4%, n = 21; 14.1 ± 1.7 %, n = 12).…”

Section: Resultsmentioning

confidence: 99%

Differential degradation of motor deficits during gradual dopamine depletion with 6-hydroxydopamine in mice

2015

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Parkinson’s disease (PD) is a movement disorder whose cardinal motor symptoms arise due to the progressive loss of dopamine. Although this dopamine loss typically progresses slowly over time, currently there are very few animal models that enable incremental dopamine depletion over time within the same animal. This type of gradual dopamine depletion model would be useful in studies aimed at the prodromal phase of PD, when dopamine levels are pathologically low but motor symptoms have not yet presented. Utilizing the highly characterized neurotoxin 6-hydroxydopamine (6-OHDA), we have developed a paradigm to gradually deplete dopamine levels in the striatum over a user-defined time course – spanning weeks to months – in C57BL/6 mice. Dopamine depletions were achieved by administration of five low dose injections (0.75 µg) of 6-OHDA through an implanted intracranial bilateral cannula targeting the medial forebrain bundle. Levels of dopamine within the striatum declined linearly with successive injections, quantified using tyrosine hydroxylase immunostaining and high-performance liquid chromatography. Behavioral testing was carried out at each time point to study the onset and progression of motor impairments as a function of dopamine loss over time. We found that spontaneous locomotion, measured in an open field, was robust to loss of dopamine until ~70% of striatal dopamine was lost. Beyond this point, additional dopamine loss caused a sharp decline in motor performance, reaching a final level comparable to that of acutely depleted mice. Similarly, although rearing behavior was more sensitive to dopamine loss and declined linearly as a function of dopamine levels, it eventually declined to levels similar to that seen in acutely depleted mice. In contrast, motor coordination, measured on a vertical pole task, was only moderately impaired in gradually depleted mice, despite severe impairments observed in acutely depleted mice. These results demonstrate the importance of the temporal profile of dopamine loss on the magnitude and progression of behavioral impairments. Our gradual depletion model thus establishes a new paradigm with which to study how circuits respond and adapt to dopamine loss over time, information which could uncover important cellular events during the prodromal phase of PD that ultimately impact the presentation or treatability of behavioral symptoms.

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Section: Resultsmentioning

confidence: 99%

Differential degradation of motor deficits during gradual dopamine depletion with 6-hydroxydopamine in mice

2015

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“…44 GABA is the major inhibitory neurotransmitter in the basal ganglia, and abnormalities of GABAergic transmission are key aspects of the pathophysiology of movement disorders that involve the basal ganglia. 51 Additionally, it has been identified that voluntary exercise can increase levels of BDNF. BDNF has neurotrophic and neuroprotective properties, can enhance brain plasticity and appears to be a prime candidate for mediating the long-term benefits of exercise on the brain.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Exercise Training in Improving Motor Performance and Corticomotor Excitability in People With Early Parkinson's Disease

Fisher

Salem

et al. 2008

Archives of Physical Medicine and Rehabilitation

376

325

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Objectives-To obtain preliminary data on the effects of high-intensity exercise on functional performance in people with Parkinson's disease (PD) relative to exercise at low and no intensity; and to determine whether improved performance is accompanied by alterations in corticomotor excitability as measured through transcranial magnetic stimulation (TMS).Design-Cohort (prospective), randomized controlled trial. Setting-University-based clinical and research facilities.Participants-Thirty people with PD, 3 years or more since diagnosis, with Hoehn and Yahr stage 1 or 2.Interventions-Subjects were randomized to high-intensity exercise using body weight-supported treadmill training, low-intensity exercise, or a zero-intensity education group. Subjects completed 24 exercise sessions over 8 weeks and had 5 education classes over 8 weeks. Main Outcome Measures-UnifiedParkinson's Disease Rating Scales (UPDRS), biomechanic analysis of self-selected, fast walking, and sit-to-stand tasks; corticomotor excitability was assessed with cortical silent period durations (CSP) in response to single-pulse TMS.Results-A small improvement in total and motor UPDRS was observed in all groups. Highintensity group subjects demonstrated postexercise increases in gait speed, step and stride length, and hip and ankle joint excursion during self-selected and fast gait and improved weight distribution No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated. SuppliersPublisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptArch Phys Med Rehabil. Author manuscript; available in PMC 2010 November 22. Published in final edited form as:Arch Phys Med Rehabil. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript during sit-to-stand. Improvements in gait and sit-to-stand measures were not consistently observed in low-and zero-intensity groups. Importantly, the high-intensity group demonstrated lengthening in CSP.Conclusions-The findings suggest the dose-dependent benefits of exercise and that highintensity exercise can normalize corticomotor excitability in early PD. KeywordsBasal ganglia; Central nervous system; Neuronal plasticity; Rehabilitation; Walking Both basic research and clinical studies suggest that high intensity (ie, high repetition, velocity, complexity) is a characteristic of exercise that may be important in promoting activitydependent neuroplasticity of the injured brain, includin...

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“…Moreover, various genome-wide gene expression analyses in the striatum of human and mouse models have shown that a number of differentially expressed genes are involved in neurotransmission, including GABAergic signaling (Kuhn et al, 2007;Seredenina and Luthi-Carter, 2012). GABAergic pathways dominate information processing in most areas of the basal ganglia (Galvan and Wichmann, 2007). Diversity in GABAergic signaling is due to several pre-and post-synaptic factors and GABA handling in and around the synapse (Buddhala et al, 2009;Mortensen et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Early GABAergic transmission defects in the external globus pallidus and rest/activity rhythm alteration in a mouse model of Huntington’s disease

Chazalon

Bestaven

et al. 2016

Neuroscience

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GABAergic circuits in the basal ganglia and movement disorders

Cited by 61 publications

References 251 publications

Differential degradation of motor deficits during gradual dopamine depletion with 6-hydroxydopamine in mice

Differential degradation of motor deficits during gradual dopamine depletion with 6-hydroxydopamine in mice

The Effect of Exercise Training in Improving Motor Performance and Corticomotor Excitability in People With Early Parkinson's Disease

Early GABAergic transmission defects in the external globus pallidus and rest/activity rhythm alteration in a mouse model of Huntington’s disease

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