Spine classification analysis revealed

a higher fraction of filopodia-like and thin spines compared to stubby and mushroom spines in Fmr1 KO neurons. In contrast, the fraction of filopodia-like spines was significantly decreased with a concomitant elevation of mature stubby/mushroom spines in dKO neurons, comparable to levels in WT and S6K1 KO neurons ( Figure 5C). No appreciable differences were found in spines of other types ( Figure S5). These findings demonstrate that removing S6K1 can counteract dendritic morphology abnormalities associated with loss of FMRP. To assess whether the genetic reduction of S6K1 in Fmr1 KO mice could alleviate autistic-like behaviors, we performed an array of tests on all four genotypes. It has been reported that the behavior of Fmr1 KO mice in these tests Roxadustat ic50 is sensitive to genetic background, age, and GSK2118436 concentration the experimental paradigms used ( Dobkin et al., 2000; Spencer et al., 2011). Therefore, we designed our behavioral battery to include tests that have reported consistent differences between WT and Fmr1 KO mice and have been conducted previously in our laboratory ( Hoeffer et al., 2008). To examine motor coordination and skill acquisition, we tested performance on the rotarod using parameters similar to those described previously (Spencer et al., 2011). Fmr1 KO mice were significantly impaired in learning and motor coordination across eight trials over two days as compared to their WT littermates

( Figure 6A). In contrast, the dKO mice displayed markedly higher motor coordination and acquisition, performing consistently

better than the other three genotypes on both days of the test ( Figure 6A). Motor coordination and acquisition of S6K1 KO mice was diminished, which differs from previous findings ( Antion et al., 2008b), perhaps due to background differences. Taken together, the rotarod results indicate that removal of S6K1 corrects impaired motor coordination and motor skill acquisition in FXS model mice. Deficits in appropriate L-NAME HCl social interaction and perspective taking are one of the core features of autism spectrum disorders (ASDs). Therefore, we employed the three-chambered social interaction test to determine whether removal of S6K1 could prevent impaired/inappropriate social behavior shown by Fmr1 KO mice. In the social approach test, experimental mice interacted more with the stimulus mouse compared to the object across all genotypes ( Figure S6D). When the object was replaced by a novel mouse in the next phase of the test, clear genotype-specific differences emerged ( Figure 6C). Fmr1 KO mice failed to distinguish between the familiar and novel mice, whereas WT and dKO mice spent significantly more time interacting with the novel mouse. S6K1 KO mice showed a trend toward increased interaction with novel stimuli. These findings indicate that removing S6K1 can correct deficits in social interactions displayed by FXS model mice.