Altered function of glutamatergic cortico-striatal synapses causes output pathway abnormalities in a chronic model of parkinsonism

Warre, Ruth; Thiele, Sherri L.; Talwar, Sheena; Kamal, Marium; Johnston, Tom H.; Wang, Sharon; Lam, Doris; Lo, Charlotte; Khademullah, C. Sahara; Perera, Gillian; Reyes, Gabriela; Sun, Xuan; Brotchie, Jonathan M.; Nash, Joanne E.

doi:10.1016/j.nbd.2010.10.013

Cited by 32 publications

(33 citation statements)

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“…Other groups have also generated mouse models of LID; however, the mortality rate was not reported in these studies, thus, it is not possible to compare this aspect of our study with these previous studies Fasano et al, 2010). Previous studies have proved the BAC transgenic mice that express eGFP driven by striatal output pathway specific promoters (direct pathway: eGFP-D1; indirect pathway: eGFP-D2 and eGFP-A2A) (Gong et al, 2003) to be extremely useful for studying the two striatal output pathways in isolation, and have provided invaluable information with regards to the synaptic changes that occur in parkinsonism (Kreitzer and Malenka, 2007;Shen et al, 2008;Warre et al, 2011). Combining the mouse model of LID described in the current study with these BAC transgenic mice will be extremely useful for studying the cellular and molecular mechanisms underlying LID in the direct and indirect striatal output pathways.…”

Section: Discussionmentioning

confidence: 91%

“…These BAC transgenic mice have been used to show that there are output pathway specific pathological changes in synaptic plasticity in parkinsonian mice (Kreitzer and Malenka, 2007;Shen et al, 2008;Warre et al, 2011). Indirect evidence suggests that pathological changes in synaptic plasticity at the level of the direct and indirect striatal output pathways may also underlie LID (Ahmed et al, 2010;Belujon et al, 2010;Ghiglieri et al, 2010;Guigoni and Bezard, 2009;Picconi et al, 2003Picconi et al, , 2008Pisani and Shen, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Generation of a model of l-DOPA-induced dyskinesia in two different mouse strains

Thiele

Warre

Khademullah

et al. 2011

Journal of Neuroscience Methods

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Generation of a model of l-DOPA-induced dyskinesia in two different mouse strains

Thiele

Warre

Khademullah

et al. 2011

Journal of Neuroscience Methods

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“…Spontaneous rotational behaviour was performed 14 days following 6-OHDA-lesion surgery, when nigro-striatal degeneration has reached a maximum and is stable (Warre et al, 2011). For assessment of spontaneous rotational behaviour, mice were placed in glass cylinders (11 × 9.5 cm), and their activity was immediately recorded for 40 min using a video camera.…”

Section: Methodsmentioning

confidence: 99%

Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse models

Thiele

Chen

et al. 2014

Neurobiology of Disease

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Parkinsonian symptoms arise due to over-activity of the indirect striatal output pathway, and under-activity of the direct striatal output pathway. l-DOPA-induced dyskinesia (LID) is caused when the opposite circuitry problems are established, with the indirect pathway becoming underactive, and the direct pathway becoming over-active. Here, we define synaptic plasticity abnormalities in these pathways associated with parkinsonism, symptomatic benefits of l-DOPA, and LID. We applied spike-timing dependent plasticity protocols to corticostriatal synapses in slices from 6-OHDA-lesioned mouse models of parkinsonism and LID, generated in BAC transgenic mice with eGFP targeting the direct or indirect output pathways, with and without l-DOPA present. In naïve mice, bidirectional synaptic plasticity, i.e. LTP and LTD, was induced, resulting in an EPSP amplitude change of approximately 50% in each direction in both striatal output pathways, as shown previously. In parkinsonism and dyskinesia, both pathways exhibited unidirectional plasticity, irrespective of stimulation paradigm. In parkinsonian animals, the indirect pathway only exhibited LTP (LTP protocol: 143.5 ± 14.6%; LTD protocol 177.7 ± 22.3% of baseline), whereas the direct pathway only showed LTD (LTP protocol: 74.3 ± 4.0% and LTD protocol: 63.3 ± 8.7%). A symptomatic dose of l-DOPA restored bidirectional plasticity on both pathways to levels comparable to naïve animals (Indirect pathway: LTP protocol: 124.4± 22.0% and LTD protocol: 52.1± 18.5% of baseline. Direct pathway: LTP protocol: 140.7 ± 7.3% and LTD protocol: 58.4 ± 6.0% of baseline). In dyskinesia, in the presence of l-DOPA, the indirect pathway exhibited only LTD (LTP protocol: 68.9 ± 21.3% and LTD protocol 52.0 ± 14.2% of baseline), whereas in the direct pathway, only LTP could be induced (LTP protocol: 156.6 ± 13.2% and LTD protocol 166.7 ± 15.8% of baseline). We conclude that normal motor control requires bidirectional plasticity of both striatal outputs, which underlies the symptomatic benefits of l-DOPA. Switching from bidirectional to unidirectional plasticity drives global changes in striatal pathway excitability, and underpins parkinsonism and dyskinesia.

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“…In models of Parkinson disease (PD), for example, the loss of DA and inhibitory D 2 receptor signaling triggers a rapid and profound pruning of corticostriatal synapses in iSPNs, ostensibly in an attempt to reduce spiking (68). This adaptation is not entirely successful, and there are a host of secondary changes in intrinsic excitability and dendritic morphology that evolve over the weeks following lesioning dopaminergic fibers (69). Even though the principal target of the dopaminergic innervation lost in PD is the striatum, the response to its loss spreads to other parts of the basal ganglia with time.…”

Section: Homeostatic Alterations In Network Activitymentioning

confidence: 99%

Brain networks in Huntington disease

Eidelberg¹,

Surmeier²

2011

J. Clin. Invest.

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Recent studies have focused on understanding the neural mechanisms underlying the emergence of clinical signs and symptoms in early stage Huntington disease (HD). Although cell-based assays have focused on cell autonomous effects of mutant huntingtin, animal HD models have revealed alterations in the function of neuronal networks, particularly those linking the cerebral cortex and striatum. These findings are complemented by metabolic imaging studies of disease progression in premanifest subjects. Quantifying metabolic progression at the systems level may identify network biomarkers to aid in the objective assessment of new disease-modifying therapies and identify new regions that merit mechanistic study in HD models. Neuropathology in Huntington diseaseHuntington disease (HD) is caused by expansion of a CAG repeat in the huntingtin (Htt) gene. Expansion of the repeat length beyond 35 CAGs significantly elevates disease risk (1). The Htt gene is ubiquitously expressed in the brain with relative enrichment in cortical pyramidal neurons projecting to the striatum but relatively low levels in striatal projection neurons (2, 3).Although there are clear effects in the cerebral cortex and hippocampus, the most pronounced neuropathology in HD is found in the striatum (4, 5). The striatum is a key component of the basal ganglia, an interconnected set of subcortical nuclei involved in the regulation of how to act (and not act) in particular contexts (6). The striatum is composed primarily of GABAergic projection neurons with dendrites that are heavily studded with spines. These spiny projection neurons (SPNs) can be subdivided into two major classes on the basis of their axonal projection, dendritic size, and physiology as well as their expression of dopamine receptors and releasable peptides (7,8). SPNs that project to the external segment of the globus pallidus (GPe) form what is called the indirect SPN (iSPN) pathway because they indirectly control the nuclei that interface between the basal ganglia and the rest of the brain. SPNs that project to the internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata form the direct SPN (dSPN) pathway. iSPNs are smaller and more excitable than dSPNs (Figure 1 and ref. 9); this difference is very likely to reflect a tonic negative modulation of iSPNs by dopamine acting at D 2 receptors. In contrast, dSPNs are positively modulated by D 1 receptors that appear to only be activated by transient elevations in dopamine release produced by bursts of action potentials in dopaminergic neurons (10).iSPNs and dSPNs are generally thought to play complementary roles in movement control and action selection. Both SPN populations have a rich, highly convergent synaptic connectivity with glutamatergic neurons distributed throughout much of the cerebral cortex (11). Both populations also have rich connectivity with glutamatergic neurons in the thalamus (12). A broad array of experimental evidence supports the proposition that iSPNs help to suppress cortical selection of...

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Altered function of glutamatergic cortico-striatal synapses causes output pathway abnormalities in a chronic model of parkinsonism

Cited by 32 publications

References 86 publications

Generation of a model of l-DOPA-induced dyskinesia in two different mouse strains

Generation of a model of l-DOPA-induced dyskinesia in two different mouse strains

Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse models

Brain networks in Huntington disease

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