Shedding light on dyskinesias.

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.