Cholinergic control of striatal neurons to modulate L‐dopa‐induced dyskinesias

Abstract

L-dopa induced dyskinesias (LIDs) are a disabling motor complication of L-dopa therapy for Parkinson's disease (PD) management. Treatment options remain limited and the underlying network mechanisms remain unclear due to a complex pathophysiology. What is well-known, however, is that aberrant striatal signaling plays a key role in LIDs development. Here, we discuss the specific contribution of striatal cholinergic interneurons (ChIs) and GABAergic medium spiny projection neurons (MSNs) with a particular focus on how cholinergic signaling may integrate multiple striatal systems to modulate LIDs expression. Enhanced ChI transmission, altered MSN activity and the associated abnormal downstream signaling responses that arise with nigrostriatal damage are well known to contribute to LIDs development. In fact, enhancing M4 muscarinic receptor activity, a receptor favorably expressed on D1 dopamine receptor-expressing MSNs dampens their activity to attenuate LIDs. Likewise, ChI activation via thalamostriatal neurons is shown to interrupt cortical signaling to enhance D2 dopamine receptor-expressing MSN activity via M1 muscarinic receptors, which may interrupt ongoing motor activity. Notably, numerous preclinical studies also show that reducing nicotinic cholinergic receptor activity decreases LIDs. Taken together, these studies indicate the importance of cholinergic control of striatal neuronal activity and point to muscarinic and nicotinic receptors as significant pharmacological targets for alleviating LIDs in PD patients.

Striatal Dopamine D2-Muscarinic Acetylcholine M1 Receptor–Receptor Interaction in a Model of Movement Disorders

“…Five distinct mAChR subtypes (M 1 R-M 5 R) have been identified, which are classified into two groups, based on pharmacological and molecular characteristics. The excitatory M 1 -like receptors (M 1 R, M 3 R, and M 5 R) transduce their signals via G q/11 proteins, whereas the inhibitory M 2 -like receptors (M 2 R and M 4 R) are coupled to G i/o proteins (Zhang et al, 2002;Bordia and Perez, 2019). All subtypes are present in the striatum, with M 1 R and M 4 R being highly expressed and modulating the excitability of GABAergic MSNs (Hersch et al, 1994;Yan et al, 2001).…”

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

“…Interestingly, positive effects of ChIs photoinhibition are also observed on cognitive and affective alterations (anxiety, visuospatial short-term memory) induced by partial striatal DA depletion, mimicking the premotor phase of PD (Ztaou et al, 2018), suggesting that the DA-ACh imbalance may also be present in the early stages of the disease. In addition, striatal ChIs appear to be crucial to the expression of L-DOPA-induced dyskinesia and optogenetic activation of striatal ChIs regulates their expression (Bordia and Perez, 2018;Bordia et al, 2016).…”

Functional characterization of AC5 gain-of-function variants: Impact on the molecular basis of ADCY5-related dyskinesia

“…The initiation and control of movement by the striatum is dependent upon a complex system of neural circuitry and requires delicately balanced GPCR and adenylyl cyclase signaling (9). D 1 R expressing MSNs of the direct pathway project to and inhibit the substantia nigra pars reticulata (SNr) to promote movement, whereas activation of the D 2 R MSNs of the indirect striatopallidal pathway results in the suppression of movement (9,10). The importance of maintaining this balance is highlighted by recent exome sequencing results that identified novel gain-of-function mutations in the gene coding for AC5 in patients with a movement disorder initially named "familial dyskinesia and facial myokymia (FDFM)" but presently referred to as ADCY5-related dyskinesia (MIM606703) since the phenotypic spectrum has been more extensively studied (11)(12)(13)(14).…”