Fig. 2: LRRK2 interferes with haloperidol-induced adaptations in indirect pathway SPNs.

A Schematic of the proposed timeline for synaptic and cell-intrinsic adaptations with haloperidol treatment based on a synthesis of current and prior findings. Some of the schematics were created with BioRender.com. B Cataleptic response of WT mice receiving haloperidol, or haloperidol + MLi-2, at 7 and 14 days following treatments. Haloperidol-treated mice develop tolerance to catalepsy after 14 but not 7 days of haloperidol administration. N = 15, 14, 13, 16 mice, in order of groups presented. The 7- and 14-day regimen data are from panels 1B and Supplementary Fig. 1G, respectively. C Left, Example of confocal maximum projection image of an Adora2a^Cre SPN expressing AAV5/DIO-EGFP. Scale bar = 15 μm. Right, Examples of dendritic segments in different treatment conditions. Scale bar = 10 μm. D Summary graph of dendritic spine density in iSPNs across treatments. N = 14–20 cells, 3 mice/group. E Example current clamp recording traces in response to a 150 pA current injection in iSPNs of WT mice after 14 days of treatment, as noted. Recordings were performed 24–48 h after the final injection. Insets: scale 4 mV, 20 ms. F Summary data show decreased cellular excitability with haloperidol, rescued to control levels by LRRK2 inhibition. Scale, as noted. N = 14–29 cells, 3–6 mice/condition. Data are represented as mean ± SEM. Asterisks in B show statistical significance for Tukey’s multiple comparison tests after two-way ANOVA; *p < 0.05. D shows statistical significance for Tukey’s multiple comparison tests after one-way ANOVA **p < 0.01, ****, p < 0.0001. Asterisks in F show statistical significance after two-way ANOVA with multiple comparisons. Large asterisk, interaction between treatment and current steps. Small asterisks, significance at specific current steps, determined by Sidak multiple comparisons. *p < 0.05, **p < 0.01, ***p < 0.001. Error bars as SEM.