Figure 1.

Lovastatin, not simvastatin, corrects fragile X phenotypes. A, Data from Osterweil et al. (2013) and Muscas et al. (2019) were combined and re-analyzed. Metabolic labeling was performed on hippocampal slices prepared from WT/Fmr1^-/y littermates as previously described. A dose-response curve shows lovastatin corrects excess protein synthesis in the Fmr1^-/y hippocampus at 50 μm (two-way repeated measures mixed-model ANOVA treatment p = 0.0052, genotype p = 0.0006, genotype × treatment p = 0.0438; Sidak’s WT veh vs KO veh *p = 0.0021, KO veh vs KO 50 *p = 0.0014). In contrast, simvastatin significantly raises protein synthesis in a dose-dependent manner in both Fmr1^-/y and WT hippocampus (two-way repeated measures mixed-model ANOVA treatment p < 0.0001, genotype p = 0.0005, genotype × treatment p = 0.9754, Sidak’s WT veh vs WT 0.5 *p = 0.0120, WT veh vs WT 5 *p < 0.0001, KO veh vs KO 0.5 *p = 0.0157, KO veh vs KO 5 *p < 0.0001). B, Data re-plotted from Muscas et al. (2019; Extended Data Figure 1-1). AGS assays show that acute injection of 100 mg/kg lovastatin significantly reduces the incidence of seizures in Fmr1^-/y mice versus vehicle control (Fisher’s exact test *p = 0.0136). Conversely, neither an equipotent dose of 50 mg/kg simvastatin (Fisher’s exact test p = 0.6968) nor a lower 3 mg/kg dose significantly (Fisher’s exact test p > 0.999) impacts the incidence of seizures in the Fmr1^-/y mouse. C, AGS results from Muscas et al. (2019) and Osterweil et al. (2013) show that although simvastatin fails to reduce seizures, lovastatin significantly reduces seizures when given at 10 mg/kg orally for 2 d, 30 mg/kg injection (intraperitoneal), or 100 mg/kg injection (intraperitoneal) in Fmr1^-/y mice on both C57BL6 and FVB background strains (Fisher’s exact test: 10 mg/kg *p = 0.003, 30 mg/kg *p = 0.041, 100 mg/kg C57 *p = 0.005, 100 mg/kg FVB *p = 0.005; Extended Data Figs. 1-2, 1-3).