Contribution of cholinergic interneurons to striatal pathophysiology in Parkinson's disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder caused by the loss of nigral dopaminergic neurons innervating the striatum, the main input structure of the basal ganglia. This creates an imbalance between dopaminergic inputs and cholinergic interneurons (ChIs) within the striatum. The efficacy of anticholinergic drugs, one of the earliest therapy for PD before the discovery of L-3,4-dihydroxyphenylalanine (L-DOPA) suggests an increased cholinergic tone in this disease. The dopamine (DA)-acetylcholine (ACh) balance hypothesis is now revisited with the use of novel cutting-edge techniques (optogenetics, pharmacogenetics, new electrophysiological recordings). This review will provide the background of the specific contribution of ChIs to striatal microcircuit organization in physiological and pathological conditions. The second goal of this review is to delve into the respective contributions of nicotinic and muscarinic receptor cholinergic subunits to the control of striatal afferent and efferent neuronal systems. Special attention will be given to the role played by muscarinic acetylcholine receptors (mAChRs) in the regulation of striatal network which may have important implications in the development of novel therapeutic strategies for motor and cognitive impairment in PD.

Strategies for the Treatment of Parkinson’s Disease: Beyond Dopamine

“…Striatal ChIs appear to support synaptic plasticity and cognitive functions, mediated by the dorsal striatum such as attention, and motivation (Bohnen and Albin, 2011;Deffains and Bergman, 2015;Aarsland, 2016;Aarsland et al, 2017;Schapira et al, 2017a). ChIs and DA work together to regulate motor function and represent good targets to alleviate PD symptoms (Ztaou and Amalric, 2019). In the striatum, ChIs express the muscarinic acetylcholine receptors (mAChRs; M1/M5) as well as various subtypes of nAChRs, composed mainly of α4, α6, α7, β2, and β3 subunits, with the primary expression of the α4β2 and α6β2 receptors (Quik and Wonnacott, 2011).…”

Striatal Cholinergic Interneurons: How to Elucidate Their Function in Health and Disease

“…This further adds to the view that CIN dysfunctional activity contributes to the pathophysiology of PD. Indeed, there is good evidence to suggest that the loss of DA in the striatum modifies the cholinergic signalling (Tanimura, 2018;McKinley, 2019;Ztaou and Amalric, 2019) and increases the correlated activity between CINs (Raz, 2001). Although the minimal neuronal circuit generating the parkinsonian beta synchronizations in basal ganglia circuits are not known, it is possible that CIN activity represents a good candidate to promote synchronized activity in these neuronal networks.…”

“…Activation of mAChRs modulates an array of voltage-gated channels and intracellular pathways in MSNs. Determining the combinatorial effect of these actions, potentially even opposing each other, is highly challenging and has recently been covered at length by excellent recent reviews (Tanimura, 2018;Ztaou and Amalric, 2019;Abudukeyoumu et al, 2019). A hallmark of CINs is their continuous tonic activity, which is expected to lead to a high level of ACh in the striatum, and the stereotypical bursts and pauses activity that they acquire during sensorimotor learning (Apicella, 2007).…”

Optogenetics in Brain Research: From a Strategy to Investigate Physiological Function to a Therapeutic Tool

“…Indeed, L-DOPA induced dyskinesia (LIDs) is a crucial compliance for Parkinson's pharmacological treatments. Optogenetic stimulation of striatal cholinergic system [113,119] led to a reduction of LIDs symptoms. Even in this work, different stimulation modalities imply opposite results-short pulse optical stimulation (1-5 ms) increased LIDs (the forelimb use decreased from 59.4 ± 4% after only L-DOPA treatment to 58.3 ± 7.5% total after short stimulation), while longer pulse optical stimulation (20 ms-1 s) significantly decreased LIDs in parkinsonian mice (the forelimb use increased up to 61.6 ± 1.8% total compared to only L-DOPA treatment showed before) [119].…”

“…Since PD is related to an excitatory/inhibitory imbalance in the BG circuits [112], therapeutic optogenetic applications can target several neuronal populations at BG levels, from MSNs involved in direct and indirect pathways to glutamatergic neurons in the subthalamic nucleus (STN). Moreover, optogenetics offers a range of strategies that cover both excitation and inhibition modulation with high spatial resolution [113], as in the case of Yoon et al that performed optical STN inhibition using halorhodopsin (NpHR). This condition led to an improvement in forelimb akinesia in a unilateral mouse model of PD [61] (the use of the contralateral forelimb was 9.8 ± 6.3% in the control group vs 38.8 ± 8.1% in NpHR group during stimulation), suggesting that the STN inactivation could reduce the firing pattern of output nuclei as GPi and SNr and leading an improvement in motor symptoms.…”