Striatal activation by optogenetics induces dyskinesias in the 6‐hydroxydopamine rat model of Parkinson disease

Hernández, Ledia F.; Castela, Ivan; Ruiz-DeDiego, Irene; Obeso, José A.; Moratalla, Rosario

doi:10.1002/mds.26947

Cited by 51 publications

(50 citation statements)

References 31 publications

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“…Recently, the basic assumptions of Albin and colleagues have been tested experimentally in the mouse using cell type-specific optogenetic or chemogenetic stimulation methods. Overall, these studies have verified the notion that hyperactivity of iSPNs suppresses movement, whereas a large activation of dSPNs can elicit movement (Kravitz et al 2010) and also lead to dyskinesia (Perez et al 2017; Hernandez et al 2017; Alcacer et al 2017). Using different types of designer receptor exclusively activated by designer drugs (DREADD), Alcacer and colleagues have shown that the mode of dSPN activation is critical to the emergence of abnormal involuntary movements.…”

Section: The Striatummentioning

confidence: 61%

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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Section: The Striatummentioning

confidence: 61%

On the neuronal circuitry mediating l-DOPA-induced dyskinesia

2018

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“…Recent studies demonstrated that optical or chemogenetic stimulation of sensorimotor MSNs in parkinsonian animals can evoke dyskinesia (Alcacer et al, 2017; Hernández et al, 2017; Perez et al, 2017); dyskinesias have also been reported with dMSN stimulation in healthy animals (Rothwell et al, 2015). These observations suggest synchronous activation of many dMSNs in the sensorimotor striatum may be sufficient to cause dyskinesia but do not indicate which neurons are normally engaged in LID.…”

Section: Discussionmentioning

confidence: 99%

A Subpopulation of Striatal Neurons Mediates Levodopa-Induced Dyskinesia

Girasole

Lum

Nathaniel

et al. 2018

Neuron

106

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SUMMARY Parkinson’s disease is characterized by the progressive loss of midbrain dopamine neurons. Dopamine replacement therapy with levodopa alleviates parkinsonian motor symptoms but is complicated by the development of involuntary movements, termed levodopa-induced dyskinesia (LID). Aberrant activity in the striatum has been hypothesized to cause LID. Here, to establish a direct link between striatal activity and dyskinesia, we combine optogenetics and a method to manipulate dyskinesia-associated neurons, targeted recombination in active populations (TRAP). We find that TRAPed cells are a stable subset of sensorimotor striatal neurons, predominantly from the direct pathway, and that reactivation of TRAPed striatal neurons causes dyskinesia in the absence of levodopa. Inhibition of TRAPed cells, but not a nonspecific subset of direct pathway neurons, ameliorates LID. These results establish that a distinct subset of striatal neurons is causally involved in LID and indicate that successful therapeutic strategies for treating LID may require targeting functionally selective neuronal subtypes.

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“…Whereas the study of Perez and colleagues suggests that the selective activation of direct pathway MSNs is sufficient to induce dyskinesia, Hernández and colleagues demonstrate that concomitant activation of direct and indirect pathways is equally able to induce optodyskinesias, suggesting that activation of the indirect pathway does not seem to counteract this effect.…”

mentioning

confidence: 96%

“…In this issue of Movement Disorders, two interesting studies report the results of in vivo optogenetic approaches in rodents, to address the mechanisms underlying the induction of dyskinesia . In the first study, Hernández and colleagues have used optogenetic stimulation of the striatum to induce dyskinesias in a hemiparkinsonian model of PD in rats .…”

mentioning

confidence: 99%