Aberrant Striatal Activity in Parkinsonism and Levodopa-Induced Dyskinesia

Publication date: 19 June 2018
Source:Cell Reports, Volume 23, Issue 12
Author(s): Michael B. Ryan, Chloe Bair-Marshall, Alexandra B. Nelson
Action selection relies on the coordinated activity of striatal direct and indirect pathway medium spiny neurons (dMSNs and iMSNs, respectively). Loss of dopamine in Parkinson's disease is thought to disrupt this balance. While dopamine replacement with levodopa may restore normal function, the development of involuntary movements (levodopa-induced dyskinesia [LID]) limits therapy. How chronic dopamine loss and replacement with levodopa modulate the firing of identified MSNs in behaving animals is unknown. Using optogenetically labeled striatal single-unit recordings, we assess circuit dysfunction in parkinsonism and LID. Counter to current models, we found that following dopamine depletion, iMSN firing was elevated only during periods of immobility, while dMSN firing was dramatically and persistently reduced. Most notably, we identified a subpopulation of dMSNs with abnormally high levodopa-evoked firing rates, which correlated specifically with dyskinesia. These findings provide key insights into the circuit mechanisms underlying parkinsonism and LID, with implications for developing targeted therapies.

Graphical abstract

Teaser

Parkinson's disease and dopamine replacement therapy are associated with marked alterations in dopaminergic signaling. Ryan et al. show that chronic dopamine loss and dopamine replacement with levodopa bidirectionally modulate the firing of direct and indirect pathway neurons and that a subset of direct pathway neurons exhibits high levodopa-evoked firing rates correlated with dyskinesia severity.


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