Figure 5. Partial inhibition of HCN and SK channels is sufficient to mimic changes in ChI activity after lesion and chronic L-DOPA treatment.

(A) Proposed changes in HCN and SK currents in ChIs from different treatment groups and their effect on spontaneous firing rates (+). (B) Dependence of I_h density (as measured on Figure 3E) on ZD7288 concentration. The orange curve represents fit of the data with the equation Y = 100(X^Slope)/(IC₅₀^Slope + X^Slope). Hill slope and IC₅₀ are 0.9 and 1.4 µM, correspondingly; n = 8 neurons/2 mice. (C) Dependence of mAHP current density (as measured on Figure 4C) on apamin concentration. Hill slope and IC₅₀ are 4 and 0.9 nM, correspondingly; n = 6 neurons/2 mice.(D–G) Partial SK and HCN channel blockade reproduced changes in the sAP rate and coefficient of variation of 6-OHDA and +chronic-LD groups. Although on average the decrease and increase in sAP frequency caused by apamin+ZD and apamin alone, respectively, did not reach statistical significance (D), apamin+ZD reliably decreased and apamin alone increased baseline sAP firing rate in individual ChIs (E). Likewise, the differences in the median coefficient of variation did not reach statistical significance (F), however, apamin+ZD increased CV over baseline for most ChIs, whereas apamin alone did not change the baseline CV (G). Untreated n = 17 neurons/6 mice, apamin+ZD n = 8 neurons/3 mice, apamin n = 10 neurons/3 mice; In panel D, p<0.001 (***) by Kruskal-Wallis test with Dunn’s multiple comparisons. In panels E and G, p<0.05 (*) and p<0.01 (**), Wilcoxon matched-pairs signed rank test.