Genetic deletion of S6K1 in Fmr1 KO mice was successful in correcting numerous behavioral abnormalities, including social interaction, novel object recognition, and behavioral flexibility ( Figure 6). Our analyses also revealed that S6K1 KO

mice themselves display impaired novel object recognition ( Figure 6B) and abnormal social behavior ( Figure 6C). In contrast, S6K1 KO mice were adept at reversal learning in the Y-maze ( Figures 6D and 6E). In addition, S6K1 KO mice were hypoactive in the open field arena ( Figures S3A and S3B) as reported earlier ( Antion et al., 2008b) but were impaired in rotarod performance ( Figure 6A). We chose to limit our biochemical, electrophysiological, CH5424802 order and morphological studies to the hippocampus due to the extensive data available in this brain area for Fmr1 KO mice. However, many of the behavioral tests we conducted have well-established cortical-, striatal-, and amygdala-dependent selleck products components. We observed no rescue of FXS-associated hyperactivity and marble-burying features in dKO mice, suggesting that there is limited impact of deleting S6K1 on altered corticostriatal circuitry in FXS model mice. However, impairments in novel social and object recognition were rectified, suggesting that the S6K1 removal may results in region-specific correction of cortical impairments in FXS mice. It will

be important to examine molecular and synaptic phenotypes

in other brain regions to obtain a more holistic idea of how the lack of S6K1 wields a corrective influence on the FXS brain. Though FXS is largely considered a disorder of the nervous system, FMRP expression is widespread during development, with postnatal expression limited to neurons and testes (Hinds et al., 1993). This suggests a possible role for nonneuronal FMRP in peripheral phenotypes, the effects of which are felt even of after the actual protein expression has abated. This may be the reason why strategies based on neuronal mediators do not rescue peripheral symptoms such as macro-orchidism and connective tissue abnormalities entirely (Dölen et al., 2007; Michalon et al., 2012). Thus, the correction of macro-orchidism in the dKO mice was likely because S6K1 was constitutively and globally reduced across tissues and organ systems in FXS mice. It remains to be determined whether connective tissue defects in the Fmr1 KO mice also are rescued by deletion of S6K1. We propose that the translational control of specific mRNAs in neurons is dynamically regulated by the opposing actions of FMRP and S6K1 (Figure 8). In WT mice, signaling downstream of cell surface receptors activate mTORC1 and/or ERK that results in activation of S6K1, which promotes protein synthesis via phosphorylation of multiple downstream effectors (Figure 8A).