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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. © 2022 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Enhanced striatal cholinergic interneuron activity contributes to the striatal hypercholinergic state in Parkinson's disease (PD) and to levodopa‐induced dyskinesia. In severe PD, dyskinesia and motor fluctuations become seriously debilitating, and the therapeutic strategies become scarce. Given that the systemic administration of anticholinergics can exacerbate extrastriatal‐related symptoms, targeting cholinergic interneurons is a promising therapeutic alternative. Therefore, unraveling the mechanisms causing pathological cholinergic interneuron activity in severe PD with motor fluctuations and dyskinesia may provide new molecular therapeutic targets. Methods: We used ex vivo electrophysiological recordings combined with pharmacological and morphological studies to investigate the intrinsic alterations of cholinergic interneurons in the 6‐hydroxydopamine mouse model of PD treated with levodopa. Results: Cholinergic interneurons exhibit pathological burst‐pause activity in the parkinsonian "off levodopa" state. This is mediated by a persistent ligand‐independent activity of dopamine D1/D5 receptor signaling, involving a cyclic adenosine monophosphate (cAMP) pathway. Dysregulation of membrane ion channels that results in increased inward‐rectifier potassium type 2 (Kir2) and decreased leak currents causes the burst pause activity, which can be dampened by pharmacological inhibition of intracellular cAMP. A single challenge with a dyskinetogenic dose of levodopa is sufficient to induce persistent cholinergic interneuron burst‐pause firing. Conclusion: Our data unravel a mechanism causing aberrant cholinergic interneuron burst‐pause activity in parkinsonian mice treated with levodopa. Targeting D5‐cAMP signaling and the regulation of Kir2 and leak channels may alleviate parkinsonism and dyskinesia by restoring normal cholinergic interneuron function. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]