What’s wrong with the striatal cholinergic interneurons in Parkinson’s disease? Focus on intrinsic excitability

Abstract

Parkinson's disease (PD) is characterized by a degeneration of nigrostriatal dopaminergic neurons that results in a hypercholinergic state in the striatum. This hypercholinergic state contributes to the clinical signs of PD. However, the mechanisms that underlie this state remain unknown. Cholinergic interneurons (ChIs) are the main source of acetylcholine in the striatum. Many studies have highlighted the importance of their normal physiological activity to guarantee a normal motor control and goal-directed behaviour. Moreover, recent studies with optogenetic and chemogenetic approaches have shown that reducing ChIs activity ameliorates parkinsonian symptoms and modifies L-dopa induced dyskinesia in PD animal models. Here, we review the described alterations in ChIs physiology that may contribute to a hypercholinergic state in PD. The best-established finding is an increase of ChIs intrinsic membrane excitability after dopaminergic denervation of striatum. Understanding the molecular basis of ChIs dysfunction in PD could help to develop new therapeutic tools to restore their normal activity and decrease parkinsonian symptoms, improving life quality of PD patients.

The cryptic gonadotropin-releasing hormone neuronal system of human basal ganglia

“…Parkinson's disease (PD) is characterized by motor symptoms such as abnormal involuntary movements, bradykinesia, rigidity, gait, and tremor. Non-motor symptoms often include cognitive impairment, mood disorders, sleep alterations, dysautonomia, anosmia and hallucinations (Perez-Lloret & Barrantes, 2016;Tubert & Murer, 2020). Many of these malfunctions in PD can be explained with the loss of the nigrostriatal dopaminergic input and ameliorated with levodopa.…”

“…These data indicate involvement of other neurotransmitter systems. In particular, loss of striatal dopamine input causes a local hypercholinergic state in the striatum with consequences reviewed recently (Tubert & Murer, 2020). This hypercholinergic state explains the success of early PD therapies with atropa belladonna derivatives (Goetz, 2011).…”

“…This hypercholinergic state explains the success of early PD therapies with atropa belladonna derivatives (Goetz, 2011). Although the low efficacy of anticholinergic drugs compared to levodopa and unwanted side effects limit the use of general anticholinergic strategies (Katzenschlager et al, 2003), selective inhibition of striatal ChINs has been proposed recently as a more promising strategy to improve the transmitter balance in dopamine-deprived basal ganglia (Mallet et al, 2019;Tubert & Murer, 2020). An important physiological mechanism to inhibit acetylcholine release from ChINs is via M2-type (M2 and M4) muscarinic autoreceptors coupled to Gi proteins.…”

Inhibition of cholinergic interneurons potentiates corticostriatal transmission in D1 receptor-expressing medium-sized spiny neurons and restores motor learning in parkinsonian condition

“…Measurement of ACh concentration in brain samples has been particularly challenging due its rapid hydrolyzation by acetylcholinesterase, likely explaining the conflicting results obtained with this technique. Similarly, the increase in spontaneous CIN activity that would be expected with a hypercholinergic state has not been clearly established in PD models (Tubert and Murer, 2021). However, other mechanisms such as aberrant synchronization (Raz et al, 2001) or alteration of RGS4-dependent auto-receptors (Ding et al, 2006) may explain the increased impact of cholinergic transmission in PD.…”

Special Issue Editorial: Basal Ganglia/Movement Disorders

“…In their review, Martel and Apicella (2020) discuss the functional interplay between the nigrostriatal dopaminergic system and striatal cholinergic interneurons that regulates temporal processing in the striatum. This is followed by the review of Tubert and Murer that describes the alterations in cholinergic interneuron physiology that may contribute to the hyper‐cholinergic state in PD (Tubert & Murer, 2020). Two additional studies examined the role of cholinergic interneurons in the regulation of striatal GABAergic projection neurons and interneurons using computational modelling.…”