A Subpopulation of Striatal Neurons Mediates Levodopa-Induced Dyskinesia

Girasole, Allison E; Lum, Matthew; Nathaniel, Diane; Bair-Marshall, Chloe J.; Guenthner, Casey J.; Luo, Liqun; Kreitzer, Anatol C.; Nelson, Alexandra

doi:10.1016/j.neuron.2018.01.017

Cited by 98 publications

(104 citation statements)

References 43 publications

(51 reference statements)

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“…Our findings reveal transcriptional distinctions that demarcate PF cell-type classes and also separate it from its neighboring medial dorsal nucleus in the anterior-posterior axis and the posterior nucleus in medial-lateral axis. Thus, these results permit targeted analyses of specific PF subcircuits and neuron classes in normal behavior and disease-models, similar to studies already underway in other brain regions(Svoboda and Li, 2018) (Beyeler et al, 2018) (Wallace et al, 2017) (Saunders et al, 2015) (Girasole et al, 2018) (Mastro et al, 2014) but not previously possible in the ILM of the TH.…”

supporting

confidence: 63%

Distinct Cortical-Thalamic-Striatal Circuits Through the Parafascicular Nucleus

Mandelbaum

Taranda

Haynes

et al. 2018

Preprint

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The thalamic parafascicular nucleus (PF), an excitatory input to the basal ganglia, is targeted with deep-brain-stimulation to alleviate a range of neuropsychiatric symptoms.Furthermore, PF lesions disrupt the execution of correct motor actions in uncertain environments. Nevertheless, the circuitry of the PF and its contribution to action selection are poorly understood. We find that, in mice, PF forms the densest subcortical projection to the striatum. This projection arises from transcriptionally-and physiologically-distinct classes of PF neurons that are also reciprocally connected with functionally-distinct cortical regions, differentially innervate striatum neurons, and are not synaptically connected in PF. Thus, mouse PF contains heterogeneous neurons that are organized into parallel and independent associative, limbic, and motor circuits. Furthermore, these subcircuits share motifs of cortical-PF-cortical and cortical-PF-striatum organization that allow each PF subregion, via its precise connectivity with cortex, to coordinate diverse inputs to striatum.

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supporting

confidence: 63%

Distinct Cortical-Thalamic-Striatal Circuits Through the Parafascicular Nucleus

Mandelbaum

Taranda

Haynes

et al. 2018

Preprint

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“…For instance, Alcacer et al () found dyskinesia scores resembling those observed in LID when chemogenetic activation of dMSN was combined with a D 2 receptor agonist, suggesting that inhibition of iMSN by D 2 receptors is necessary for full expression of LID. Furthermore, a genetic model allowing to “trap” active neurons during LID recruited mainly dMSN but also iMSN (Girasole et al, ), and recent studies show modulations of activity in both dMSN and iMSN during LID (Parker et al, ; Ryan et al, ). However, optostimulation of striatonigral axon terminals can cause more powerful dyskinesia than moderate and even high doses of L‐DOPA, which cannot be further increased by combining optostimulation with L‐DOPA.…”

Section: Discussionmentioning

confidence: 99%

Optostimulation of striatonigral terminals in substantia nigra induces dyskinesia that increases after L‐DOPA in a mouse model of Parkinson's disease

Keifman

Ruiz-DeDiego

Pafundo

et al. 2019

British J Pharmacology

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Background and Purpose L‐DOPA‐induced dyskinesia (LID) remains a major complication of L‐DOPA therapy in Parkinson's disease. LID is believed to result from inhibition of substantia nigra reticulata (SNr) neurons by GABAergic striatal projection neurons that become supersensitive to dopamine receptor stimulation after severe nigrostriatal degeneration. Here, we asked if stimulation of direct medium spiny neuron (dMSN) GABAergic terminals at the SNr can produce a full dyskinetic state similar to that induced by L‐DOPA. Experimental Approach Adult C57BL6 mice were lesioned with 6‐hydroxydopamine in the medial forebrain bundle. Channel rhodopsin was expressed in striatonigral terminals by ipsilateral striatal injection of adeno‐associated viral particles under the CaMKII promoter. Optic fibres were implanted on the ipsilateral SNr. Optical stimulation was performed before and 24 hr after three daily doses of L‐DOPA at subthreshold and suprathreshold dyskinetic doses. We also examined the combined effect of light stimulation and an acute L‐DOPA challenge. Key Results Optostimulation of striatonigral terminals inhibited SNr neurons and induced all dyskinesia subtypes (optostimulation‐induced dyskinesia [OID]) in 6‐hydroxydopamine animals, but not in sham‐lesioned animals. Additionally, chronic L‐DOPA administration sensitised dyskinetic responses to striatonigral terminal optostimulation, as OIDs were more severe 24 hr after L‐DOPA administration. Furthermore, L‐DOPA combined with light stimulation did not result in higher dyskinesia scores than OID alone, suggesting that optostimulation has a masking effect on LID. Conclusion and Implications This work suggests that striatonigral inhibition of basal ganglia output (SNr) is a decisive mechanism mediating LID and identifies the SNr as a target for managing LID.

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“…These and other data (Bateup et al 2010; Fasano et al 2010; Heiman et al 2014; Suarez et al 2018, 2016) indicate that changes in dSPN activity driven by concomitant strong activation of ERK1/2 and cAMP/PKA signaling are key to the emergence of involuntary movements. Further implicating the critical role of direct pathway overactivity in LID, a recent study has reported that a stable group of dSPNs in the dorsolateral striatum are very active during the expression of dyskinesia, and that optogenetically inhibiting these neurons significantly reduces the severity of LID (Girasole et al 2018). Notwithstanding the pivotal role of the direct pathway, LID involves pronounced synaptic remodelling of iSPNs (Fieblinger et al 2014; Suarez et al 2014, 2018, 2016) and it is improved by chemogenetic stimulation of these neurons (Alcacer et al 2017).…”

Section: The Striatummentioning

confidence: 99%

On the neuronal circuitry mediating l-DOPA-induced dyskinesia

2018

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With the advent of rodent models of l-DOPA-induced dyskinesia (LID), a growing literature has linked molecular changes in the striatum to the development and expression of abnormal involuntary movements. Changes in information processing at the striatal level are assumed to impact on the activity of downstream basal ganglia nuclei, which in turn influence brain-wide networks, but very little is actually known about systems-level mechanisms of dyskinesia. As an aid to approach this topic, we here review the anatomical and physiological organisation of cortico-basal ganglia-thalamocortical circuits, and the changes affecting these circuits in animal models of parkinsonism and LID. We then review recent findings indicating that an abnormal cerebellar compensation plays a causal role in LID, and that structures outside of the classical motor circuits are implicated too. In summarizing the available data, we also propose hypotheses and identify important knowledge gaps worthy of further investigation. In addition to informing novel therapeutic approaches, the study of LID can provide new clues about the interplay between different brain circuits in the control of movement.

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A Subpopulation of Striatal Neurons Mediates Levodopa-Induced Dyskinesia

Cited by 98 publications

References 43 publications

Distinct Cortical-Thalamic-Striatal Circuits Through the Parafascicular Nucleus

Distinct Cortical-Thalamic-Striatal Circuits Through the Parafascicular Nucleus

Optostimulation of striatonigral terminals in substantia nigra induces dyskinesia that increases after L‐DOPA in a mouse model of Parkinson's disease

On the neuronal circuitry mediating l-DOPA-induced dyskinesia

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