Levodopa Causes Striatal Cholinergic Interneuron Burst‐Pause Activity in Parkinsonian Mice

Abstract

A BS TRACT: 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.

Non-uniform distribution of dendritic nonlinearities differentially engages thalamostriatal and corticostriatal inputs onto cholinergic interneurons

“…Importantly, dendrites are positioned at the interface between synaptic inputs and the intrinsic properties of CIN. While changes in synaptic transmission and intrinsic excitability of CINs have received attention in models of PD, HD and other movement disorders ( Abudukeyoumu et al, 2019 ; Aceves Buendia et al, 2019 ; Choi et al, 2020 ; Ding et al, 2006 ; Ding et al, 2011 ; Eskow Jaunarajs et al, 2015 ; Mallet et al, 2019 ; Paz et al, 2021 ; Pisani et al, 2007 ; Plotkin and Goldberg, 2019 ; Poppi et al, 2021 ; Tanimura et al, 2019 ; Tubert and Murer, 2021 ), studying alterations in dendritic excitability in these models is a complementary approach that remains largely unchartered territory.…”

Non-uniform distribution of dendritic nonlinearities differentially engages thalamostriatal and corticostriatal inputs onto cholinergic interneurons

“…Importantly, dendrites are positioned at the interface between synaptic inputs and the intrinsic properties of CIN. While changes in synaptic transmission and intrinsic excitability of CINs have received attention in models of PD, HD and other movement disorders (Abudukeyoumu et al, 2019; Aceves Buendia et al, 2019; Choi et al, 2020; Ding et al, 2006, 2011; Eskow Jaunarajs et al, 2015; Mallet et al, 2019; Paz et al, 2021; Pisani et al, 2007; Plotkin and Goldberg, 2019; Poppi et al, 2021; Tanimura et al, 2019; Tubert and Murer, 2021), studying alterations in dendritic excitability in these models is a complementary approach that remains largely unchartered territory.…”

Current approaches to characterize micro- and macroscale circuit mechanisms of Parkinson’s disease in rodent models

“…Combining patch-clamp recordings with high frequency electrical stimulation (HFS) in the STN could show that it led to long-lasting changes in postsynaptic currents and burst behaviour in the downstream globus pallidus interna (GPi) ( Ammari et al, 2011 ; Luo et al, 2018 ). In the striatum (STR), patch-clamp recordings combined with the application of dopamine was able to identify the molecular mechanisms underlying physiological and pathological spiking patterns which could be associated to levodopa (L-DOPA) induced dyskinesia (LID) ( McKinley et al, 2019 ; Paz et al, 2021 ). Beyond active spiking properties, patch-clamp recordings also allow extensive characterization of intrinsic electrophysiological properties together with detailed morphological reconstruction of neurons in PD models ( Branch et al, 2016 ; Choi et al, 2020 ; Tubert et al, 2016 ).…”