Fig. 4

Effect of PLX3397 on module 18 expression and seizures. a PLX3397 regulates module 18 genes. Epileptic mice were treated daily for 7 days with vehicle or PLX3397 at 3 or 30 mg/kg per day (n = 8 mice in each group). At the end of the treatment, hippocampal RNA was extracted and the expression of marker genes in modules 18 and 22 was assayed by rt-qPCR. Module 18 marker genes were significantly down-regulated by PLX3397 at 30 mg/kg per day (*P < 0.05, **P < 0.01—one-tailed Welch’s t test). b Restoration of module 18 expression in epilepsy toward health by PLX3397. Epileptic mice were treated with PLX3397 at 3 or 30 mg/kg per day or vehicle alone (n = 8 mice in each group). Hippocampal mRNA was extracted on day 14 of treatment and module 18 expression assayed by microarray. Red line indicates the linear negative correlation between the two conditions compared to a theoretical complete restoration of expression toward the healthy state (dotted black line). Treatment with PLX3397 resulted in a significant and dose-dependent (P = 3.6 × 10⁻¹⁴) restoration of expression of module 18 toward health (i.e., toward the dotted black diagonal). c Efficacy of PLX3397 on seizures—pilocarpine model. Epileptic mice were baseline monitored for a week (white) before daily administration with vehicle or PLX3397 at 3 or 30 mg/kg per day (n = 20 mice in each group) and monitored for a second week (black). PLX3397 treatment induced a significant decrease in daily seizure frequency (**P < 0.01—Wilcoxon's signed-rank test) at 30 mg/kg per day. d Efficacy of PLX3397 on paroxysmal hippocampal discharges—kainate model. Epileptic mice (n = 8) were EEG monitored at baseline (day 0) for 2 h prior to daily administration of PLX3397 at 30 mg/kg per day for 4 days and then EEG monitored on day 5 for 2 h to assess drug efficacy. Treatment with PLX3397 led to a significant (*P < 0.05) reduction in the duration of HPDs. e Efficacy of PLX3397 in organotypic hippocampal slice cultures. (i) Representative field potential traces of ictal epileptiform activity in dentate gyrus (DG) granular cell layer following 2 weeks of vehicle alone or 1 µM PLX3397, (ii) mean and (iii) duration of ictal events (±S.E.M.) at baseline (DIV 8) and following PLX3397 (DIV 15 and DIV 22). (iv) supernatant concentrations (mean ± S.E.M.) of lactate dehydrogenase at baseline (DIV 7) and following PLX3397 (DIV 14 and DIV 21). In total, 60 hippocampal slices from six rats were analyzed consisting of 36 slices for control and 24 for PLX3397 treatment groups, respectively. *P < 0.05