Decrease of K ATP channel expression through D3 receptor-mediated GSK3β signaling alleviates levodopa-induced dyskinesia (LID) in Parkinson's disease mouse model.

Aims: The standard Parkinson's disease (PD) treatment is L-3,4-dihydroxyphenylalanine (L-DOPA); however, its long-term use may cause L-DOPA-induced dyskinesia (LID). Aberrant activation of medium spiny neurons (MSNs) contributes to LID, and MSN excitability is regulated by dopamine D3 receptor (D3R) and ATP-sensitive potassium (K _ATP ) channel activity. Nevertheless, it remains unclear if D3R and K _ATP channels may be linked in the context of LID.
Methods: Wild-type and tyrosine hydroxylase (TH)-specific Kir6.2 knockout mice were injected with 6-hydroxydopamine (6-OHDA) to generate a PD mouse model, then chronically treated with L-DOPA to induce LID. Analyses included immunohistochemical staining, biochemical endpoints, and behavior tests. The mechanisms by which D3R/K _ATP channels regulate LID in the PD/LID mouse model were probed by treatment with a D3R antagonist, K _ATP channel opener and glycogen synthase kinase 3β (GSK3β) inhibitor, followed by evaluation of abnormal involuntary movements (AIMs).
Key Findings: The D3R antagonist FAUC365 alleviated LID, reducing AIMs and protecting against degeneration of the nigrostriatal pathway, which occurred through a direct interaction between D3Rs and K _ATP channels. In line with this mechanism, activation of D3R/GSK3β signaling increased K _ATP channel expression in the striatum of PD/LID mice. Additionally, the K _ATP channel opener Diz slowed LID progression and preserved nigrostriatal projections. Consistently, mice with TH-specific knockout of Kir6.2 exhibited reduced PD-like symptoms and less severe LID.
Significance: D3Rs act through GSK3β signaling to regulate expression of K _ATP channels, which may subsequently modulate LID. Inhibition of K _ATP channels in TH-positive cells is sufficient to reduce AIMs in a mouse model of PD/LID.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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