Shedding light on dyskinesias

Abstract

Dopamine replacement therapy with L-DOPA remains the most widely prescribed treatment for Parkinson disease. However, prolonged treatment due to disease progression frequently causes unwanted motor movements known as levodopa-induced dyskinesias. Previous studies have established that alterations to the efferent circuitry of the striatum, a principal component of the basal ganglia, are in part responsible for the pathological motor consequences of prolonged levodopa treatment. While the role of the striatal direct pathway is widely accepted, the engagement of the striatal indirect pathway in dyskinetic pathophysiology is still under consideration. However, recent investigations have finally shown that the activity of both striatal pathways changes as a consequence of dopamine depletion and dyskinetic behavioural conditions. In addition, it has been reported that drug-induced structural alterations to indirect pathway medium spiny neurons, together with associated changes in synaptic plasticity and firing patterns, could contribute importantly to the development of dyskinesia. These findings, together with recent opto-and chemogenetic studies, suggest that a critical imbalance in the activity between both striatal pathways is sufficient to cause dyskinesia in both rodent and primate models of Parkinson disease.In animal models, and in human patients, dyskinetic behaviours elicited by this efferent pathway imbalance can be achieved even in the absence of dopamine denervation. In this review, we summarize recent and past findings to better understand this complex pathology with the aim of pursuing specific cell-type therapies to re-balance efferent striatal activity.

Simultaneous Measurement of Striatal Dopamine and Hydrogen Peroxide Transients Associated with L-DOPA Induced Rotation in Hemiparkinsonian Rats

“…This could suppress the ectopic release of L-DOPA-derived DA in the denervated striatum, as these channels are expressed on a multitude of cellular subtypes. 56 Both dopamine D1 and D2 receptors are implicated in dyskinesias, 57,58 but activation of D1-receptor containing MSNs (D1R-MSNs) is sufficient to induce dyskinetic behavior. 59,60 Indeed, in vivo photometry studies in genetically modified mice have shown transient increases in MSN activity that precede and predict (within 500 ms) the start of contraversive movements.…”

“…Both dopamine D1 and D2 receptors are implicated in dyskinesias, , but activation of D1-receptor containing MSNs (D1R-MSNs) is sufficient to induce dyskinetic behavior. , Indeed, in vivo photometry studies in genetically modified mice have shown transient increases in MSN activity that precede and predict (within 500 ms) the start of contraversive movements . Furthermore, a recent study in mice has used the targeted recombination in active population (TRAP) strategy to demonstrate that a specific subset of striatal cells (mostly direct pathway D1R-MSNs) is reliably activated with dyskinetic behavior associated with L-DOPA. , Optogenetic activation of these TRAP-ed cells elicited AIMs and contraversive rotations .…”

Molecular Pathophysiological Mechanisms in Huntington’s Disease

“…However, there are other differences between MSNs in the direct and indirect pathways as well, aside from the dopaminergic receptors they express. In vitro studies have shown differences in resting membrane potential, excitability, threshold for action potential generation [ 273 ], and morphologic differences relating to the dendritic surface area [ 274 ].…”

Morphological and functional changes of striatal neurons with L‐dopa‐induced dyskinesia

“…Dopaminergic denervation and repeated L‐dopa treatment induce plastic changes involving both direct and indirect pathway SPNs. It remains unclear whether changes in the neuronal activity or morphology (dendritic spine pathology) of indirect pathway SPNs are associated with dyskinesia or are just a therapeutic effect of L‐dopa 49 . However, recent evidence suggests that functional changes within the indirect pathway may be also involved in LID.…”