Figure 5.

Inhibiting GSK3α does not overcome audiogenic seizure treatment resistance induced by chronic CTEP. (A) Some elements of the signaling pathway that couples mGluR5 to protein synthesis. AGS susceptibility in fragile X can be corrected by the protein synthesis inhibitor CHX and by compounds acting at several different nodes in this pathway, including GSK3α. (B) Schematic shows drug dosing schedule and AGS experimental design. (C) Chronic (3 doses over 5 days) treatment with 2.0 mg/kg CTEP followed by a vehicle injection does not alter Fmr1-KO audiogenic seizure susceptibility (two-tailed Fisher’s exact test: Fmr1-KO 4x vehicle vs. Fmr1-KO 3x CTEP +1x vehicle p = 0.4267). A single injection of 30 mg/kg BRD0705 normalizes audiogenic seizure susceptibility in Fmr1-KO mice but has no effect on seizure incidence in Fmr1-KO mice treated with chronic (3 doses over 5 days) 2.0 mg/kg CTEP (two-tailed Fisher’s exact test: Fmr1-KO 4x vehicle vs. Fmr1-KO 3x vehicle + BRD0705 p = 0.0036; two-tailed Fisher’s exact test: Fmr1-KO 4x vehicle vs. Fmr1-KO 3x CTEP + BRD0705 p = 0.2357).