Switching on the lights of dyskinesia: Perspectives and limits of the optogenetic approaches

Picconi, Barbara; Calabresi, Paolo

doi:10.1002/mds.26999

Cited by 5 publications

(5 citation statements)

References 15 publications

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“…Hernández, Castela, Ruiz-DeDiego, Obeso, & Moratalla, 2017;Perez, Zhang, Bordia, & Quik, 2017). Altogether, this work suggests that loss of dopamine input can modify striatal circuit function such that striatal activation induces dyskinesia instead of normal actions (Picconi & Calabresi, 2017).…”

mentioning

confidence: 83%

“…Furthermore, optogenetic or chemogenetic stimulation of severely dopamine‐denervated striatal neurons in L‐DOPA‐naïve rodents can induce dyskinesia resembling LID (Alcacer et al, ; F. Hernández, Castela, Ruiz‐DeDiego, Obeso, & Moratalla, ; Perez, Zhang, Bordia, & Quik, ). Altogether, this work suggests that loss of dopamine input can modify striatal circuit function such that striatal activation induces dyskinesia instead of normal actions (Picconi & Calabresi, ).…”

Section: Introductionmentioning

confidence: 89%

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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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mentioning

confidence: 83%

Section: Introductionmentioning

confidence: 89%

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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“…SCIN burst‐pauses synchronized to bursts of DAN activity 14 likely mediates circuit changes involved in reinforcement learning 15 . Distortion of this coordinated ACh/DA interplay could be partly responsible for abnormal synaptic plasticity, morphology, and excitability observed in striatal medium spiny neurons (MSN) in animal models of LID 16‐20 . While some of the membrane mechanisms underlying the burst‐pause discharge pattern have been disclosed, 12 how DAN degeneration and l ‐dopa administration lead to alterations of SCIN physiology remains unanswered.…”

Section: Introductionmentioning

confidence: 99%

D1/D5 Inverse Agonists Restore Striatal Cholinergic Interneuron Physiology in Dyskinetic Mice

Paz

Tubert

2022

Movement Disorders

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A BS TRACT: Background: In advanced stages of Parkinson's disease (PD), dyskinesia and motor fluctuations become seriously debilitating and therapeutic options become scarce. Aberrant activity of striatal cholinergic interneurons (SCIN) has been shown to be critical to PD and dyskinesia, but the systemic administration of cholinergic medications can exacerbate extrastriatal-related symptoms. Thus, targeting the mechanisms causing pathological SCIN activity in severe PD with motor fluctuations and dyskinesia is a promising therapeutic alternative. Methods: We used ex vivo electrophysiological recordings combined with pharmacology to study the alterations in intracellular signaling that contribute to the altered SCIN physiology observed in the 6-hydroxydopamine mouse model of PD treated with levodopa. Results: The altered phenotypes of SCIN of parkinsonian mice during the "off levodopa" state resulting from aberrant Kir/leak and Kv1.3 currents can be rapidly reverted by acute inhibition of cAMP-ERK1/2 signaling. Inverse agonists that inhibit the ligand-independent activity of D5 receptors, like clozapine, restore Kv1.3 and Kir/leak currents and SCIN normal physiology in dyskinetic mice. Conclusion: Our work unravels a signaling pathway involved in the dysregulation of membrane currents causing SCIN hyperexcitability and burst-pause activity in parkinsonian mice treated with levodopa (L-dopa). These changes persist during off-medication periods due to tonic mechanisms that can be acutely reversed by pharmacological interventions. Thus, targeting the D5-cAMP-ERK1/2 signaling pathway selectively in SCIN may have therapeutic effects in PD and dyskinesia by restoring the normal SCIN function.

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“…The most common treatment consists of dopamine replacement (e.g. levodopa=L-DOPA), which not only loses its full efficacy in a few years but may also induce severe dyskinesia (Picconi et al, 2017). Hence more studies on etiology as well as development of more efficacious interventions aiming at neuroprotection are urgently needed.…”

Section: Introductionmentioning

confidence: 99%

Nicotine protects against manganese and iron-induced toxicity in SH-SY5Y cells: Implication for Parkinson's disease

Getachew

Csóka

Aschner

et al. 2019

Neurochemistry International

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Manganese (Mn) and iron (Fe) are trace elements that are essential for proper growth and physiological functions as both play critical role in a variety of enzymatic reactions. At high concentrations, however, they can be toxic and cause neurodegenerative disorders, particularly Parkinson-like syndromes. Nicotine, on the other hand, has been shown to have neuroprotective effects against various endogenous or exogenous toxins that selectively damage the dopaminergic cells. These cells include neuroblastoma-derived SH-SY5Y cells which express significant dopaminergic activity. However, practically no information on possible neuroprotective effects of nicotine against toxicity induced by trace elements is available. Therefore, in this study we investigated the effects of nicotine on toxicity induced by manganese or iron in these cells. Exposure of SH-SY5Y cells for 24 h to manganese (20 μM) or iron (20 μM) resulted in approximately 30% and 35% toxicity, respectively. Pretreatment with nicotine (1 μM) completely blocked the toxicities of Mn and Fe. The effects of nicotine, in turn, were blocked by selective nicotinic receptor antagonists. Thus, dihydro-beta erythroidine (DHBE), a selective alpha4-beta2 subtype antagonist and methyllycaconitine (MLA), a selective alpha7 antagonist, as well as mecamylamine, a non-selective nicotinic antagonist all dose-dependently blocked the protective effects of nicotine against both Mn and Fe. These findings provide further support for the potential utility of nicotine or nicotinic agonists in Parkinson's disease-like neurodegenerative disorders, including those that might be precipitated by trace elements, such as Fe and Mn. Moreover, both alpha4-beta2 and alpha7 nicotinic receptor subtypes appear to mediate the neuroprotective effects of nicotine against toxicity induced by these two trace metals.

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Switching on the lights of dyskinesia: Perspectives and limits of the optogenetic approaches

Cited by 5 publications

References 15 publications

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

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

D1/D5 Inverse Agonists Restore Striatal Cholinergic Interneuron Physiology in Dyskinetic Mice

Nicotine protects against manganese and iron-induced toxicity in SH-SY5Y cells: Implication for Parkinson's disease

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