Abstract
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.
Highlights
In Parkinson’s disease (PD), progressive degeneration of midbrain dopamine neurons is associated with marked motor impairments, including bradykinesia, tremor, and rigidity
A typical recording session consisted of a baseline period, followed by levodopa injection (5 mg/kg; Figure S1D), which caused both dyskinesia (LID; Figures 1E and S1C) and contralesional rotations (Figure 1F)
Optogenetic labeling of dMSNs and iMSNs was achieved by expressing channelrhodopsin-2 (ChR2; Figure S1B) selectively in dMSNs or iMSNs (Gerfen et al, 2013; Gong et al, 2007) and recording responses to light pulses at the end of each session
Summary
In Parkinson’s disease (PD), progressive degeneration of midbrain dopamine neurons is associated with marked motor impairments, including bradykinesia (slowed movement), tremor, and rigidity. Levodopa is initially effective in treating PD motor deficits, but with chronic treatment the majority of patients develop drug-induced involuntary movements (Ahlskog and Muenter, 2001), known as levodopa-induced dyskinesia (LID) This clinical problem highlights the importance of identifying the circuit dysfunction that results from dopamine loss and subsequent replacement with levodopa. Direct pathway neurons (dMSNs) express the D1-like dopamine receptor (Gerfen et al, 1990), and optical activation of dMSNs inhibits basal ganglia output and increases movement (Kravitz et al, 2010). Indirect pathway neurons (iMSNs) express the D2-like dopamine receptor (Gerfen et al, 1990), and optical activation of iMSNs increases basal ganglia output and suppresses movement (Kravitz et al, 2010). While pharmacological studies in ex vivo brain slices support this hypothesis (Hernandez-Lopez et al, 1997, 2000; Planert et al, 2013), it is less clear how dopamine modulates striatal activity in vivo
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