IRL790 modulated striatal D1 neurons synaptic plasticity ameliorating levodopa-induced dyskinesia in mouse

Abstract

Objective: Levodopa (L-dopa) therapy is the principal pharmacological treatment for Parkinson's disease (PD). Nevertheless, prolonged use of this drug may result in different involuntary movement symptoms caused by the medication, referred to as levodopa-induced dyskinesia (LID). LID is associated with changes in synaptic plasticity of the D1 medium spiny neurons (MSNs) located in the dorsal striatum (dStr). Within the striatum, the amount of Dopamine D3 receptor (D3R) is notably increased in LID, demonstrating colocalization with D1R expression in neurons, and the level of D3R expression is directly related to the intensity of LID. IRL 790, as a D3R antagonist, can ameliorate LID. This study aims to explore if IRL 790 improves LID by regulating the synaptic plasticity of D1+ MSNs in dStr.

Methods: The electrophysiology and synaptic spine density of D1+ MSNs in dStr were recorded for sham mice, LID mice, and LID mice treated with IRL 790. The regulation of synaptic plasticity in LID D1+ MSNs by IRL 790 was analyzed. Behavioral tests were conducted to confirm the treatment effect of IRL 790 on LID.

Results: In LID D1+ MSNs, there was persistent abnormal LTP, absence of LTD, and an increase in spontaneous excitatory postsynaptic currents (sEPSCs). IRL 790 treatment restored normal LTP, LTD, and sEPSCs. Treatment with IRL 790 also restored the reduced dendritic spine density in D1+ MSNs of LID mice. IRL790 improved dyskinetic manifestations in LID mice.

Conclusion: IRL790 ameliorates LID by regulating the synaptic structure and functional plasticity of striatal D1+ MSNs.

Keywords: Parkinson’s disease; dopamine D3 receptor; functional plasticity; levodopa-induced dyskinesia; structural plasticity.

Figure 1

Schematic experimental protocol.

Figure 2

Assessment of PD modeling. (A) Representative movement trajectories of sham mice and PD mice model in the open field for 30 min. (B) Movement distance in the open field for 30 min. (C) Representative immunofluorescence labeling of TH in dopamine neurons within the SNc of mice with PD. (D) TH+ cells relative immunofluorescence density in the SNc. ***p < 0.001, ****p < 0.0001.

Figure 3

Total Abnormal Involuntary Movement Scores. (A) Daily total AIMs scores for the LID versus LID+IRL790 groups across days 1–7. (B) Total AIMs scores from 20 min to 160 min on day 7 for the LID and LID+IRL790 groups.

Figure 4

Rotarod test and gait analysis. (A) Duration of movement on the rotarod for mice in each group. (B) The ratio of the distance between the left and right hind paws (A) to the distance between steps of the left hind paw (B) (a/b ratio) for mice in each group. (C) Representative footprints from the gait analysis experiment for mice in each group. *p < 0.05, **p < 0.01, ****p < 0.0001.

Figure 5

Patch-clamp electrophysiological recordings of D1 MSNs. (A) Representative images of cells clamped with a patch clamp. (B) Representative sEPSCs from mice in each group. (C) Amplitude of sEPSCs in mice from each group (each group n = 10 cells from 5 mice). (D) The enhanced magnitude of LTP induced (% of baseline) and the reduced magnitude of LTD (% of baseline) in mice from each group (each group n = 10 cells from 5 mice). *p < 0.05, ***p < 0.001.

Figure 6

Dendritic spine density of D1 MSNs. (A) From left to right: representative dendritic spine morphology in sham mice; mushroom spine; thin spine; stubby spine. (B) Density of mushroom, thin, stubby, and total dendritic spines in mice from each group (each group n = 10 dendritic spines from 10 cells in 5 mice). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.