Figure 1.

BAER-101 reduces neocortical hyperexcitability and seizures in Fmr1 KO mice. (A–D) Increased duration of spontaneous UP states in neocortical slices from Fmr1 KO mice is reduced to WT levels by bath application of 1 μM BAER-101. (A) Representative extracellular multi-unit recordings from layer IV of acute neocortical slices prepared from WT or Fmr1 KO mice and preincubated for 1–1.5 h in either BAER-101 (1 μM) or vehicle (0.03% DMSO). (B) Increased duration of UP states in Fmr1 KO slices is reduced by BAER-101 [2-way ANOVA with Sidak's multiple comparison, p(genotype) < 0.0001, p(drug) = 0.004, p(interaction) = 0.22]; ***p < 0.001; *p < 0.05. (C) Amplitude of UP states was reduced by BEAR-101 but not affected by genotype and no interaction was detected [2-way ANOVA, p(genotype) = 0.2, *p(drug) = 0.015, p(interaction) = 0.61]. (D) UP state frequency was not affected by genotype or treatment [2-way ANOVA, p(genotype) = 0.95, p(drug) = 0.71, p(interaction) = 0.12]. Sample sizes for UP states were as follows (slices): WT vehicle: n = 12, WT 1BAER: n = 15, Fmr1 KO vehicle: n = 12, Fmr1 KO 1BAER: n = 16. (E) Audiogenic seizures are significantly reduced by administration of 1 mg/kg and 3 mg/kg BAER-101 (1BAER and 3BAER, respectively), 30 min before testing (Kruskal-Wallis test, p = 0.0001; Wilcoxon rank pair-wise comparisons with FDR correction: *p < 0.01). Quantification of seizure scores suggests a dose-dependent effect with stronger reduction with 3 mg/kg BAER-101. WT vehicle: n = 12, WT 1BAER: n = 10, WT 3BAER: n = 11, Fmr1 KO vehicle: n = 17, Fmr1 KO 1BAER: n = 15, Fmr1 KO 3BAER: n = 13.