Abstract
Changes in striatal cholinergic interneuron (ChI) activity are thought to contribute to Parkinson's disease pathophysiology and dyskinesia from chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, but the physiological basis of these changes is unknown. We find that dopamine lesion decreases the spontaneous firing rate of ChIs, whereas chronic treatment with L-DOPA of lesioned mice increases baseline ChI firing rates to levels beyond normal activity. The effect of dopamine loss on ChIs was due to decreased currents of both hyperpolarization-activated cyclic nucleotide-gated (HCN) and small conductance calcium-activated potassium (SK) channels. L-DOPA reinstatement of dopamine normalized HCN activity, but SK current remained depressed. Pharmacological blockade of HCN and SK activities mimicked changes in firing, confirming that these channels are responsible for the molecular adaptation of ChIs to dopamine loss and chronic L-DOPA treatment. These findings suggest that targeting ChIs with channel-specific modulators may provide therapeutic approaches for alleviating L-DOPA-induced dyskinesia in PD patients.
Highlights
The loss of dopamine (DA) neurons of the substantia nigra pars compacta results in depletion of striatal DA and the manifestation of the cardinal symptoms of Parkinson’s disease (PD)
Total L-DOPA-induced dyskinesias (LID) magnitudes were similar between the first L-DOPA dose compared to mice tested after chronic L-DOPA
Consistent with this, we found that bath exposure to dopamine increased spontaneous cholinergic interneuron (ChI) firing rate only in brain slices from the 6-OHDA and chronicLD groups, indicating that the effect of dopamine is biased towards excitation by dopamine depletion
Summary
The loss of dopamine (DA) neurons of the substantia nigra pars compacta results in depletion of striatal DA and the manifestation of the cardinal symptoms of Parkinson’s disease (PD). Using acute striatal slice electrophysiological recordings in the dorsolateral striatum prepared from DA depleted and L-DOPA treated mice, we show that changes in intrinsic properties of ChIs cause slower spontaneous firing rates following DA depletion and faster firing rates after chronic L-DOPA treatment compared to sham controls. We found that both HCN and SK current were decreased in the DA depleted condition, whereas only SK current remained depressed after chronic L-DOPA. Targeting altered activity of striatal ChIs with specific channel modulators may provide a potential therapeutic approach for the alleviation of LID in PD patients
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