Centrality of Striatal Cholinergic Transmission in Basal Ganglia Function

Abstract

Work over the past two decades revealed a previously unexpected role for striatal cholinergic interneurons in the context of basal ganglia function. The recognition that these interneurons are essential in synaptic plasticity and motor learning represents a significant step ahead in deciphering how the striatum processes cortical inputs, and why pathological circumstances cause motor dysfunction. Loss of the reciprocal modulation between dopaminergic inputs and the intrinsic cholinergic innervation within the striatum appears to be the trigger for pathophysiological changes occurring in basal ganglia disorders. Accordingly, there is now compelling evidence showing profound changes in cholinergic markers in these disorders, in particular Parkinson's disease and dystonia. Based on converging experimental and clinical evidence, we provide an overview of the role of striatal cholinergic transmission in physiological and pathological conditions, in the context of the pathogenesis of movement disorders.

Cholinergic activity and levodopa‐induced dyskinesia: a multitracer molecular imaging study

“…The α 4 β 2*‐nAChRs are the prominent subtype in the human brain. The striatum receives dense cholinergic innervation, and although striatal cholinergic interneurons are few in number, they have widespread axonal arborizations, which can directly influence motor behavior 20, 21. Among the validated ligands of nicotinic receptors, 123 I‐5‐IA shows a high affinity for the β 2 subunits22, thus providing in our case, in vivo evidence of cholinergic activity.…”

Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias

“…Our rationale for the current experiments is based on emerging studies which demonstrate that cholinergic interneurons influence striatal output and are important in the control of voluntary movements and the pathogenesis of various movement disorders (Bonsi et al, 2011; Gonzales and Smith, 2015). Of relevance to the current experiments, recent studies implicate the cholinergic system in LIDs (Ding et al, 2011; Quik et al, 2015; Won et al, 2014).…”

“…The rationale is based on several lines of evidence including studies showing a close anatomical overlap between striatal dopaminergic nerve terminals and cholinergic interneurons (Lim et al, 2014; Zhou et al, 2002). Cholinergic interneurons make up 1-3% of striatal neurons and extend large and dense axonal arbors throughout the striatum that allow them to play a pivotal role in the control of striatal function (Bonsi et al, 2011; Zhou et al, 2002). These neurons fire action potentials at a rate of 5-10 Hz in a variable but ongoing manner that includes single spiking and rhythmic bursting patterns (Aosaki et al, 1995; Raz et al, 1996; Wilson et al, 1990).…”

Substantia nigra dopaminergic neurons and striatal interneurons are engaged in three parallel but interdependent postnatal neurotrophic circuits

“…The central components of the striatal circuit are cortical glutamatergic terminals that activate striatal projection neurons (medium spiny neurons, MSN). Glutamatergic signaling is modulated by dopamine from DA SNpc cells in concert with the activity of local cholinergic interneurons (ACh) and fast‐spiking GABAergic interneurons (FS; Threlfell et al, 2010; Bonsi et al, 2011; Surmeier, Carrillo‐Reid, & Bargas, 2011; Silberberg & Bolam, 2015) that together constitute the striatal modulatory circuit. The relevance of these neuronal populations on striatal function is highlighted by the alteration of distinct neuronal types in several neurological disorders, including chorea (MSN), parkinsonism (DA SNpc), Tourette syndrome (ACh and FS), and dystonia (ACh).…”