, 1998 and Soliman

et al., 2010). The ERK phosphorylation level was significantly higher in the cortex of vehicle-treated Fmr1 KO animals compared to vehicle-treated WT littermates (KO/vehicle: 122.9% ± 9.3% of WT/vehicle; p = 0.010; Figures 3D and 3H). Chronic treatment with CTEP specifically reduced the elevated ERK activity in Fmr1 KO cortex (KO/CTEP: 89.5% ± 6.5% of WT/vehicle; KO/CTEP versus KO/vehicle; p = 0.0012) with no effect on ERK activity in WT cortex. Chronic CTEP treatment also triggered a modest increase of the total ERK expression level in Fmr1 KO mice compared to vehicle-treated KO animals (KO/CTEP: 109.0% ± 6.5%; KO/vehicle: 95.1% ± 6.0%; p = 0.013; Figure 3E). The mTOR phosphorylation level was nonsignificantly increased in vehicle-treated R428 cost Fmr1 KO animals compared to vehicle-treated WT littermates

(KO/vehicle: 109.1% ± 5.0% of WT/vehicle; p = 0.13; Figure 3F). Chronic CTEP treatment significantly reduced the mTOR phosphorylation level specifically in Fmr1 KO mice and not in WT animals (KO/CTEP: 92.0% ± 4.6% of WT/vehicle; KO/CTEP versus KO/vehicle; p = 0.006). mTOR expression levels were similar in WT and KO animals and were unchanged by treatment INCB024360 manufacturer ( Figure 3G). The postadolescent macroorchidism observed in FXS patients is reflected in elevated testis weight in Fmr1 KO mice ( The Dutch-Belgian Fragile X Consortium, 1994). Testis weight was monitored starting with drug-naive 5-week-old mice throughout 17 weeks of chronic treatment with CTEP and vehicle. Fmr1 KO mice presented significantly increased testis weight compared to WT animals at all adult ages (effect size: +32.8 mg, p < 0.001; Figure 3J; see Table S2 available online), which was partially corrected upon chronic treatment (effect size: −13.5 mg, p < 0.001). No significant differences in plasma levels of testosterone ( Figure 3K) and progesterone ( Figure 3L) were observed between genotypes and treatment groups. Chronic treatment was well tolerated by the animals independent of the genotype. There was a minimal Dipeptidyl peptidase reduction in body weight gain (Figure S1A) and a modest decrease in body

temperature of 0.5°C on average (Figure S1B) in animals receiving chronic CTEP treatment compared to vehicle in both genotypes. Chronic drug treatment for 4 weeks had no effect on the rotarod performance (Figure S1C). A small but significantly reduced grip strength in vehicle-treated Fmr1 KO compared to WT mice and in CTEP-treated mice of both genotypes compared to vehicle-treated WT mice was observed ( Figure S1D). A modified version of the Irwin battery of simple neurological and observational measures ( Irwin, 1968) did not reveal any noticeable alteration in the general fitness of the animals resulting from the mutation or the treatment ( Table S1). This study assessed the therapeutic potential of chronic pharmacological mGlu5 inhibition in a mouse model of FXS, with treatment starting in young adulthood.